Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of MCP-1 of formula (I): 
                         
or stereoisomers or pharmaceutically acceptable salts thereof, wherein X, Z, a, b, c, d, bond g, n, s, R 1 , R 2 , R 4 , R 5 , R 10 , R 12 , and R 13 , are as defined above. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using said modulators are disclosed.

This application claims the benefit of U.S. Provisional Application No.60/545,881, filed Feb. 19, 2004, incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases, allergic and autoimmune diseases, and in particular, asthma,rheumatoid arthritis, atherosclerosis, and multiple sclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998,338, 436-445 and Rollins, Blood 1997, 90, 909-928). There are two majorclasses of chemokines, CXC and CC, depending on whether the first twocysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CX₃C chemokine) that do not fall into either of the majorchemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns (reviewed in Zlotnik and OshieImmunity 2000, 12, 121): CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1α,MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72, 415-425, andLuster, New Eng. J. Med. 1998, 338, 436-445); CCR-2A and CCR-2B (or“CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2, MCP-3,MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994, 91,2752-2756, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3 (or“CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster,New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270, 19495-19500, andLuster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or “CKR-5” OR“CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, et al., Biochemistry 1996,35, 3362-3367); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba, et al.,J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or “CKR-7” or “CC-CKR-7”)[ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8 (or“CKR-8” or “CC-CKR-8”) [I-309] (Napolitano et al., J. Immunol., 1996,157, 2759-2763); CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3](Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256); and CCR-11[MCP-1, MCP-2, and MCP-4] (Schweickert, et al., J. Biol. Chem. 2000,275, 90550).

Mammalian cytomegaloviruses, herpesviruses and poxviruses have also beenshown to express, in infected cells, proteins with the bindingproperties of chemokine receptors (reviewed in: Wells and Schwartz,Curr. Opin. Biotech. 1997, 8, 741-748). Human CC chemokines, such asRANTES and MCP-3, can cause rapid mobilization of calcium via thesevirally encoded receptors. Receptor expression may be permissive forinfection by allowing for the subversion of normal immune systemsurveillance and response to infection. Additionally, human chemokinereceptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act asco-receptors for the infection of mammalian cells by microbes as with,for example, the human immunodeficiency viruses (HIV).

The chemokines and their cognate receptors have been implicated as beingimportant mediators of inflammatory, infectious, and immunoregulatorydisorders and diseases, including asthma and allergic diseases, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis (reviewed in: P. H. Carter, Current Opinion in ChemicalBiology 2002, 6, 510; Trivedi et al, Ann. Reports Med. Chem. 2000, 35,191; Saunders and Tarby, Drug Disc. Today 1999, 4, 80; Premack andSchall, Nature Medicine 1996, 2, 1174). Various studies performed todate support these implications. For example, studies completed to datehave indicated that the antagonisum of the MCP-1/CC2 interaction may beuseful in treating rheumatoid arthritis; ameliorate chronicpolyadjuvant-induced arthritis (Youssef et al., J. Clin. Invest. 2000,106, 361); collagen-induced arthritis (see Ogata et al., J. Pathol.1997, 182, 106); streptococcal cell wall-induced arthritis (Schimmer etal., J. Immunol. 1998, 160, 1466); MRL-lpr mouse model of arthritis(Gong et al., J. Exp. Med. 1997, 186, 131); atherosclerosis (Rezaie-Majdet al, Arterioscler. Thromb. Vasc. Biol. 2002, 22, 1194-1199; Gu et al.,Mol. Cell 1998, 2, 275; Gosling et al., J. Clin. Invest. 1999, 103, 773;Boring et al, Nature 1998, 394, 894; and Ni et al. Circulation 2001,103, 2096-2101); multiple sclerosis (Iarlori et al., J. Neuroimmunol.2002, 123, 170-179; Kennedy et al., J. Neuroimmunol. 1998, 92, 98; Fifeet al., J. Exp. Med. 2000, 192, 899; and Izikson et al., J. Exp. Med.2000, 192, 1075); organ transplant rejection (Reynaud-Gaubert et al., J.of Heart and Lung Transplant., 2002, 21, 721-730; Belperio et al., J.Clin. Invest. 2001, 108, 547-556; and Belperio et al., J. Clin. Invest.2001, 108, 547-556); asthma (Gonzalo et al., J. Exp. Med. 1998, 188,157; Lukacs, et al., J. Immunol. 1997, 158, 4398; and Lu et al., J. Exp.Med. 1998, 187, 601); kidney disease (Lloyd et al., J. Exp. Med. 1997,185, 1371; and Tesch et al., J. Clin. Invest. 1999, 103, 73); lupuserythematosus (Tesch et al., J. Exp. Med. 1999, 190, 1813); colitis(Andres et al., J. Immunol. 2000, 164, 6303); alveolitis (Jones, et al.,J. Immunol. 1992, 149, 2147); cancer (Salcedo et al., Blood 2000, 96,34-40); restinosis (Roque et al. Arterioscler. Thromb. Vasc. Biol. 2002,22, 554-559); inflammatory bowel disease (Reinecker et al.,Gastroenterology 1995, 108, 40; and Grimm et al., J. Leukoc. Biol. 1996,59, 804); brain trauma (King et al., J. Neuroimmunol. 1994, 56, 127; andBerman et al., J. Immunol. 1996, 156, 3017); transplant arteriosclerosis(Russell et al., Proc. Natl. Acad. Sci. USA 1993, 90, 6086); idiopathicpulmonary fibrosis (Antoniades et al., Proc. Natl. Acad. Sci. USA 1992,89, 5371); psoriasis (Deleuran et al., J. Dermatol. Sci. 1996, 13, 228;and Gillitzer et al., J. Invest. Dermatol. 1993, 101, 127); and HIV andHIV-1-associated dementia (Garzino-Demo, WO 99/46991; Doranz et al.,Cell 1996, 85, 1149; Connor et al., J. Exp. Med. 1997, 185, 621; andSmith et al., Science 1997, 277, 959). Similarly, demonstration of theimportance of the MCP-1/CCR-2 interaction has been reported in theliterature. For example, Lu et al., J. Exp. Med. 1998, 187, 601; Boringet al., J. Clin. Invest. 1997, 100, 2552; Kuziel et al., Proc. Natl.Acad. Sci. USA 1997, 94, 12053; and Kurihara et al., J. Exp. Med. 1997,186, 1757.

Small molecules including ureido-substituted cyclic amines, arylalkylcyclic amines, acyclic diamines, cyclic diamines, 4,4-disubstitutedpiperidines, 1,2,3,4-tetrahydroisoquinolines, imidazolium compounds,1,4-disubstituted piperazines and diazabicyclic compounds have beenreported in the literature as antagonists of MCP-1 and/or CCR receptors.For example, Trivedi et al, Ann. Reports Med. Chem. 2000, 35, 191;Shiota et al., WO 99/25686; Shiota et al., WO 00/69815; C. Tarby and W.Moree, WO 00/69820; P. Carter and R. Cherney, WO 02/50019; R. Cherney,WO 02/060859; Matsumoto et al., WO 03/091245; Jiao et al., WO 03/093231;Axten et al., WO 03/101970; Pennell et al., WO 03/105853; and Colon-Cruzet al., WO-02/070523. Similarly, MCP-1 and/or CCR receptor antagonisticindolopiperidines quaternary amines, spiropiperidines, 2-substitutedindoles and benzimidazoles, pyrazolone derivatives,dialkylhomopiperazines, N,N-dialkylhomopiperazines, bicyclic pyrroles,tetrahydropyranyl cyclopentyl tetrahyropyridopyridines, N-arylsulfonamides and 5-aryl pentadienamides have been reported in theliterature. For example, Forbes et al., Bioorg. Med. Chem. Lett. 2000,10, 1803; Mirzadegan et al., J. Biol. Chem. 2000, 275, 25562; Baba etal., Proc. Natl. Acad. Sci. 1999, 96, 5698; A. Faull and J. Kettle, WO00/46196; Barker et al., WO 99/07351; Barker et al., WO 99/07678; Padiaet al., U.S. Pat. No. 6,011,052; Connor et al., WO 98/06703; Shiota etal., WO 97/44329; Barker et al., WO 99/40913; Barker et al., WO99/40914; Jiao et al., WO 03/092568; Fleming et al., WO 03/99773; andCarson, et al., Cambridge Health Tech Institute Chemokine Symposium,McLean, Va., USA, 1999.

However, the foregoing reference compounds are readily distinguishedstructurally from the present invention by virtue of substantialdifferences in the terminal functionality, the attachment functionality,the core functionality, and/or nature of the bicyclic ring system.Accordingly, the prior art does not disclose nor suggest the uniquecombination of structural fragments that embody the novel compoundsdescribed herein. Furthermore, the prior art does not disclose orsuggest that the compounds of the present invention would be effectiveas MCP-1 antagonists.

It should be noted that CCR-2 is also the receptor for the chemokinesMCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338,436-445). Since it is believed that the compounds of formula (I)described herein antagonize MCP-1 by binding to the CCR-2 receptor, itmay be that these compounds of formula (I) are also effectiveantagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that aremediated by CCR-2. Accordingly, when reference is made herein to“antagonism of MCP-1,” it is to be assumed that this is equivalent to“antagonism of chemokine stimulation of CCR-2.”

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel antagonists or partialagonists/antagonists of MCP-1 receptor activity, or pharmaceuticallyacceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating rheumatoidarthritis, multiple sclerosis, and atherosclerosis, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides novel cyclic derivatives for use intherapy.

The present invention provides the use of novel cyclic derivatives forthe manufacture of a medicament for the treatment of inflammatorydiseases.

These and other features of the invention, which will become apparentduring the following detailed description, have been achieved by theinventors' discovery that compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinX, Z, a, b, c, d, bond g, n, s, R¹, R², R⁴, R⁵, R¹⁰, R¹², and R¹³, aredefined below, are effective modulators of MCP-1 and chemokine activity.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In one embodiment, the present invention provides novel compounds offormula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

-   X is selected from O or S;-   Z is selected from a bond, —C(O)NR⁸—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—,    —NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—, —NR⁸C(S)NH—, —NR⁸SO₂—,    —NR⁸SO₂NH—, —OC(O)NR⁸—, —NR⁸C(O)O—, —(CR²⁵R²⁵)_(u)—, —CR¹⁴═R¹⁴—,    —CR²⁵R²⁵C(O)—, —C(O)CR²⁵R²⁵—, —CR²⁵R²⁵C(═N—OR¹⁴)—, —O—CR¹⁴R¹⁴—,    —CR¹⁴R¹⁴—O—, —O—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—,    —CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—;    -   wherein neither Z nor R¹³ is connected to a carbon atom to which        R¹⁰ is attached;-   bond (g) is a single or double bond;-   alternatively, when n is equal to 2, the two carbon atoms may join    through a double bond;-   R¹ is selected from H, R⁶, C₁₋₆ alkyl substituted with 0-3 R⁶, C₂₋₆    alkenyl substituted with 0-3 R⁶, C₂₋₆ alkynyl substituted with 0-3    R⁶, C₆₋₁₀ aryl group substituted with 0-5 R⁶, and a 5-10 membered    heteroaryl system containing 1-4 heteroatoms selected from N, O, and    S, substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈    alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, (CR′R′)_(q)C(O)R^(4b),    (CR′R′)_(q)C(O)NR^(4a)R^(4a), (CR′R′)_(q)C(O)OR^(4b), and a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4c);-   R^(4a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, and phenyl;-   alternatively, two R^(4a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(4b), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and    phenyl;-   R^(4c), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, (CR′R′)_(r)OH,    (CR′R′)_(r)SC₁₋₅ alkyl, (CR′R′)_(r)NR^(4a)R^(4a), and    (CR′R′)_(r)phenyl;-   R⁵ is selected from H, C₁₋₆ alkyl substituted with 0-2 R^(5e),    —C(O)R^(5b), —C(O)OR^(5b), —C(O)NR^(5f)R^(5f), a C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(5e), and a 5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CR′R′)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(5e), and a (CR′R′)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, OH, SH, (CR′R′)_(r)SC₁₋₅    alkyl, (CR′R′)_(r)NR^(5f)R^(5f), a (CR′R′)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(6e);-   R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   alternatively, two R^(5f)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6d)C(O)O(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),    (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6a), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a    (CR′R′)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R⁶s on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(6a), at each occurrence, is selected from H, methyl, C₂₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(6e),    and a (CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R^(6a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O, and S;-   R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2    R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₂₋₄    haloalkyl, a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(6e), and a (CR′R′)_(r)-5-6 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, OH, SH, (CR′R′)_(r)SC₁₋₅    alkyl, (CR′R′)_(r)NR^(6f)R^(6f), and (CR′R′)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   alternatively, two R^(6f)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),    (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(7e), and a (CR′R′)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(7e);-   alternatively, two R⁷s on adjacent atoms on R² may join to form a    cyclic acetal;    -   R^(7a), at each occurrence, is independently selected from H,        methyl substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with        0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈        alkynyl substituted with 0-2 R^(7e), a (CR′R′)_(r)—C₃₋₁₀        carbocyclic residue substituted with 0-5 R^(7e), and a        (CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4        heteroatoms selected from N, O, and S, substituted with 0-2        R^(7e);-   alternatively, two R^(7a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈    alkynyl substituted with 0-2 R^(7e), a (CR′R′)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(7e), and a (CR′R′)_(r)-4-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2    R^(7e), methyl, CF₃, C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3    R^(7e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3    R^(7e), and a (CR′R′)_(r)-5-6 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, (CR′R′)_(r)cyclopropyl, Cl, F, Br, CN, (CF₂)_(r)CF₃,    (CR′R′)_(r)OC₁₋₅ alkyl, OH, C(O)OC₁₋₅ alkyl,    (CR′R′)_(r)NR^(7f)R^(7f), and acetyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   alternatively, two R^(7f)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),    —C(O)NR^(7f)R^(7f), and (CR′R′)_(r)phenyl;-   R′, at each occurrence, is independently, selected from H, methyl,    and C₂₋₆ alkyl;-   alternatively, two R′s, along with the carbon atom to which they are    attached, join to form a cyclopropyl ring;-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H, and    —C(O)—C₁₋₄ alkyl;-   R¹⁰ is independently selected from H and C₁₋₄ alkyl substituted with    0-1 R^(10b),-   R^(10b), at each occurrence, is independently selected from —OH,    —SH, —NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   alternatively, two R^(10c)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R¹² is selected from H and C₁₋₄ alkyl;-   R¹³, at each occurrence, is independently selected from H, —OH,    —NH₂, F, Cl, Br, I, —OR^(13a), N(R^(13a))₂, and C₁₋₄ alkyl    substituted with 0-3 R^(13b);-   R^(13a) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R^(13b), at each occurrence, is independently selected from —OH,    —SH, —NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c) and —NHC(O)R^(13c);-   R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁴, at each occurrence, is independently selected from H and    C₁₋₄alkyl;-   alternatively, two R¹⁴s, along with the carbon atom to which they    are attached, join to form a C₃₋₆ carbocyclic ring;-   R²⁵, at each occurrence, is independently selected from H,    C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl, NR^(25a)R^(25a),    C(O)NR^(25a)R^(25a), NR^(25a)C(O)R^(25b), NR^(25a)C(O)OR^(25b),    OC(O)NR^(25a)R^(25a), and (CHR)_(r)C(O)OR^(25b);-   alternatively, two R²⁵s, along with the carbon atom or atoms to    which they are attached, join to form a C₃₋₆ carbocyclic ring;-   R^(25a), at each occurrence, is independently selected from H, and    C₁₋₄ alkyl;-   alternatively, two R^(25a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(25b), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   a is selected from 0 and 1;-   b is selected from 0, 1, 2 and 3;-   with the proviso that a+b is selected from 1, 2 and 3;-   c is selected from 0 and 1;-   d is selected from 1, 2 and 3;-   with the proviso that c+d is selected from 2 and 3;-   n is selected from 0, 1, 2 and 3;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1, 2, 3, and    4;-   r, at each occurrence, is independently selected from 0, 1, 2, 3,    and 4;-   s is selected from 0 and 1; and-   u is selected from 1, 2 and 3.

Some preferred compounds of the present invention are those in which

-   X is selected from O or S;-   Z is selected from a bond, —C(O)NR⁸—, —NR⁹—, —NR⁸C(O)—, —NR⁸C(O)NH—,    —NR⁸SO₂—, —(CR²⁵R²⁵)_(u)—, —CR¹⁴=CR¹⁴—, and —CR²⁵R²⁵C(O)—;    -   wherein neither Z nor R¹³ is connected to a carbon atom to which        R¹⁰ is attached;-   bond (g) is a single or double bond;-   alternatively, when n is equal to 2, the two carbon atoms may join    through a double bond;-   R¹ is selected from H, R⁶, C₁₋₆ alkyl substituted with 0-3 R⁶, C₆₋₁₀    aryl group substituted with 0-5 R⁶, and a 5-10 membered heteroaryl    system containing 1-4 heteroatoms selected from N, O, and S,    substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or C₁₋₈ alkyl;-   R⁵ is selected from H and C₁₋₆ alkyl substituted with 0-2 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, F, (CF₂)_(r)CF₃,    (CR′R′)_(r)OC₁₋₅ alkyl, and (CR′R′)_(r)NR^(5f)R^(5f);-   R^(5f), at each occurrence, is selected from H and C₁₋₆ alkyl;-   alternatively, two R^(5f)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, (CR′R′)_(r)NR^(6a)R^(6a),    (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6a),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6a), C₁₋₆ haloalkyl,    (CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6    membered heterocyclic system containing 1-2 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(6e);-   R^(6a), at each occurrence, is selected from H, methyl, C₂₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(6e),    and a (CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R^(6a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O, and S;-   R^(6d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-3 R^(6e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,    (CF₂)_(r)CF₃, and (CR′R′)_(r)OC₁₋₅ alkyl;-   R^(6f), at each occurrence, is selected from H and C₁₋₅ alkyl;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, Cl, Br, F, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e),    and a (CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),    a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e),    and a (CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);-   alternatively, two R^(7a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), a    (CR′R′)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and    a (CR′R′)_(r)-4-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from methyl, C₂₋₆ alkyl    substituted with 0-3 R^(7e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-3 R^(7e), and a (CR′R′)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, Cl, F, Br, CN, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, OH,    C(O)OC₁₋₅ alkyl, (CR′R′)_(r)NR^(7f)R^(7f), and acetyl;-   R^(7f), at each occurrence, is selected from H and C₁₋₅ alkyl;-   alternatively, two R^(7f)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),    —C(O)NR^(7f)R^(7f), and (CR′R′)_(r)phenyl;-   R′, at each occurrence, is independently, selected from H, methyl,    and C₂₋₆ alkyl;-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R9 is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and —C(O)—C₁₋₄    alkyl;-   R¹⁰ is independently selected from H and C₁₋₄ alkyl substituted with    0-1 R^(10b),-   R^(10b), at each occurrence, is independently selected from —OH,    —SH, —NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   alternatively, two R^(10c)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R¹² is selected from H and C₁₋₄ alkyl;-   R¹³, at each occurrence, is independently selected from H, —OH,    —NH₂, F, Cl, Br, —OR^(13a), N(R^(13a))₂, and C₁₋₄ alkyl substituted    with 0-3 R^(13b);-   R^(13a) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R^(13b), at each occurrence, is independently selected from —OH,    —SH, —NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c);-   R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁴, at each occurrence, is independently selected from H and    C₁₋₄alkyl;-   alternatively, two R¹⁴s, along with the carbon atom to which they    are attached, join to form a C₃₋₆ carbocyclic ring;-   R²⁵, at each occurrence, is independently selected from H,    C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl, NR^(25a)R^(25a),    C(O)NR^(25a)R^(25a), NR^(25a)C(O)R^(25b), NR^(25a)C(O)OR^(25b),    OC(O)NR^(25a)R^(25a), and (CHR)_(r)C(O)OR^(25b);-   alternatively, two R²⁵s, along with the carbon atom or atoms to    which they are attached, join to form a C₃₋₆ carbocyclic ring;-   R^(25a), at each occurrence, is independently selected from H, and    C₁₋₄ alkyl;-   alternatively, two R^(25a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(25b), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl;-   a is selected from 0 and 1;-   b is selected from 0 and 1;-   with the proviso that a+b is selected from 1 and 2;-   c is selected from 0 and 1;-   d is selected from 1 and 2;-   with the proviso that c+d is selected from 2 and 3;-   n is selected from 1 and 2;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1 and 2;-   r, at each occurrence, is independently selected from 0, 1, and 2;-   s is selected from 0 and 1; and-   u is selected from 1, 2 and 3.

Some particularly preferred compounds are those in which

-   X is O;-   Z is selected from a bond, —C(O)NR⁸—, —NR⁹— and —NR⁸C(O)—;-   wherein Z is not connected to a carbon atom to which R¹⁰ is    attached;-   bond (g) is a single or double bond;-   alternatively, when n is equal to 2, the two carbon atoms may join    through a double bond;-   R¹ is selected from H, R⁶, and C₁₋₆ alkyl substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷,    wherein the aryl group is selected from phenyl and naphthyl, and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷, wherein the heteroaryl is    selected from indolyl, benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl    isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, phthalazinyl,    pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or C₁₋₈ alkyl;-   R⁵ is selected from H and C₁₋₆ alkyl;-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6a),    (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6a), and    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a);-   R^(6a), at each occurrence, is selected from H, methyl, C₂₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(6e),    and a (CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);-   alternatively, two R^(6a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(6d), at each occurrence, is selected from methyl and C₂₋₆ alkyl    substituted with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,    (CF₂)_(r)CF₃, and (CR′R′)_(r)OC₁₋₅ alkyl;-   R^(6f), at each occurrence, is selected from H and C₁₋₅ alkyl;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, Cl, Br, F, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, and a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl, a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(7e), and a (CR′R′)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   alternatively, two R^(7a)s, together with the N to which they are    attached, join to form a 3-8 membered heterocycle containing 0-1    additional heteroatoms selected from N, O and S;-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₈    alkenyl, a (CR′R′)_(r)C₃₋₆ carbocyclic residue substituted with 0-3    R^(7e), and a (CR′R′)_(r)-4-6 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from methyl, C₂₋₆ alkyl, a    (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e),    and a (CR′R′)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, Cl, F, Br, CN, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl,    C(O)OC₁₋₅ alkyl, (CR′R′)_(r)NR^(7f)R^(7f), and acetyl;-   R^(7f), at each occurrence, is selected from H and C₁₋₄ alkyl;-   R′, at each occurrence, is independently, selected from H and    methyl;-   R⁸ is H;-   R9 is H;-   R¹⁰ is independently selected from H and C₁₋₄ alkyl;-   R¹² is H;-   R¹³, at each occurrence, is H;-   R¹⁴, at each occurrence, is H;-   R²⁵, at each occurrence, is independently selected from H, OH, and    NH₂;-   a is 1;-   b is 0;-   c is 1;-   d is 1;-   n is selected from 1 and 2;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is 1;-   r, at each occurrence, is independently selected from 0 and 1; and-   u is selected from 1 and 2.

Some more particularly preferred compounds are those in which

-   X is O;-   Z is selected from a bond and —NR⁹—;-   wherein Z is not connected to a carbon atom to which R¹⁰ is    attached;-   bond (g) is a single or double bond;-   alternatively, when n is equal to 2, the two carbon atoms may join    through a double bond;-   R¹ is selected from H, R⁶, and C₁₋₆ alkyl substituted with 0-2 R⁶;-   R² is a 5-10 membered heteroaryl system containing 1-4 heteroatoms    selected from N, O, and S, substituted with 0-3 R⁷, wherein the    heteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl    isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, phthalazinyl,    pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or C₁₋₈ alkyl;-   R⁵ is selected from H and C₁₋₆ alkyl;-   R⁶, at each occurrence, is selected from C₁₋₄ alkyl,    (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH, (CH₂)_(r)O(CH₂)_(r)R^(6d),    (CH₂)_(r)C(O)(CH₂)_(r)R^(6a), (CH₂)_(r)C(O)NR^(6a)R^(6a),    (CH₂)_(r)NR^(6f)C(O)(CH₂)_(r)R^(6a), and    (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6a);-   R^(6a), at each occurrence, is selected from H, C₁₋₄ alkyl, phenyl    substituted with 0-3 R^(6e), and a 5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   alternatively, two R^(6a)s, together with the N to which they are    attached, join to form a heterocycle wherein the heterocycle is    selected from azetidinyl, pyrrolyl, piperidinyl, and morpholinyl;-   R^(6d), at each occurrence, is selected from C₁₋₄ alkyl;-   R^(6e), at each occurrence, is selected from C₁₋₄ alkyl, Cl, F,    (CF₂)_(r)CF₃, and (CH₂)_(r)OC₁₋₄ alkyl;-   R^(6f), at each occurrence, is selected from H, methyl and ethyl;-   R⁷ is selected from C₁₋₆ alkyl, phenyl substituted with 0-3 R^(7e),    Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a),    NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F,    OCF₃, C(O)R^(7b), C(O)OR^(7d), NHC(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

-   R^(7a), at each occurrence, is independently selected from H and    C₁₋₄ alkyl;-   alternatively, two R^(7a)s, together with the N to which they are    attached, join to form a heterocycle wherein the heterocycle is    selected from azetidinyl, pyrrolyl, piperidinyl, and morpholinyl;-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    CN, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₄ alkyl, C(O)OC₁₋₄ alkyl,    (CH₂)_(r)NR^(7f)R⁷E, and acetyl;-   R^(7f), at each occurrence, is selected from H, and C₁₋₄ alkyl;-   R⁹ is H;-   R¹⁰ is independently selected from H and C₁₋₄ alkyl;-   R¹² is H;-   R¹³, at each occurrence, is H;-   R¹⁴, at each occurrence, is H;-   a is 1;-   b is 0;-   c is 1;-   d is 1;-   n is selected from 1 and 2;-   p, at each occurrence, is independently selected from 0, 1, and 2;    and-   r, at each occurrence, is independently selected from 0 and 1.

Some additional more particularly preferred compounds are those in which

-   X is O;-   Z is selected from —C(O)NR⁸— and —NR⁸C(O)—;-   wherein Z is not connected to a carbon atom to which R¹⁰ is    attached;-   bond (g) is a single or double bond;-   alternatively, when n is equal to 2, the two carbon atoms may join    through a double bond;-   R¹ is selected from H, R⁶, and C₁₋₆ alkyl substituted with 0-2 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁷,    wherein the aryl group is selected from phenyl and naphthyl, and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷, wherein the heteroaryl is    selected from indolyl, benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl    isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, phthalazinyl,    pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or C₁₋₈ alkyl;-   R⁵ is selected from H and C₁₋₆ alkyl;-   R⁶, at each occurrence, is selected from C₁₋₄ alkyl,    (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH, (CH₂)_(r)O(CH₂)_(r)R^(6d),    (CH₂)_(r)C(O)(CH₂)_(r)R^(6a), (CH₂)_(r)C(O)NR^(6a)R^(6a),    (CH₂)_(r)NR^(6f)C(O)(CH₂)_(r)R^(6a), and    (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6a);-   R^(6a), at each occurrence, is selected from H, C₁₋₄ alkyl, phenyl    substituted with 0-3 R^(6e), and a 5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   alternatively, two R^(6a)s, together with the N to which they are    attached, join to form a heterocycle wherein the heterocycle is    selected from azetidinyl, pyrrolyl, piperidinyl, and morpholinyl;-   R^(6d), at each occurrence, is selected from C₁₋₄ alkyl;-   R^(6e), at each occurrence, is selected from C₁₋₄ alkyl, Cl, F,    (CF₂)_(r)CF₃, and (CH₂)_(r)OC₁₋₄ alkyl;-   R^(6f), at each occurrence, is selected from H, methyl and ethyl;-   R⁷ is selected from C₁₋₆ alkyl, phenyl substituted with 0-3 R^(7e),    Cl, Br, I, F, CN, NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a),    NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F,    OCF₃, C(O)R^(7b), C(O)OR^(7d), NHC(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

-   R^(7a), at each occurrence, is independently selected from H and    C₁₋₄ alkyl;-   alternatively, two R^(7a)s, together with the N to which they are    attached, join to form a heterocycle wherein the heterocycle is    selected from azetidinyl, pyrrolyl, piperidinyl, and morpholinyl;-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    CN, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₄ alkyl, C(O)OC₁₋₄ alkyl,    (CH₂)_(r)NR^(7f)R^(7f), and acetyl;-   R^(7f), at each occurrence, is selected from H, and C₁₋₄ alkyl;-   R⁸ is H;-   R¹⁰ is independently selected from H and C₁₋₄ alkyl;-   R¹² is H;-   R¹³, at each occurrence, is H;-   R¹⁴, at each occurrence, is H;-   a is 1;-   b is 0;-   c is 1;-   d is 1;-   n is selected from 1 and 2;-   p, at each occurrence, is independently selected from 0, 1, and 2;    and-   r, at each occurrence, is independently selected from 0 and 1.

Some even more particularly preferred compounds are those in which thecompounds of formula (I) are selected from the compounds of Table 1.

In another embodiment, the present invention is directed to apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of Formula(I). The preferred, particularly preferred, more particularly preferred,and even more particularly preferred compounds set forth above can beused in this embodiment.

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I). The preferred, particularlypreferred, more particularly preferred, and even more particularlypreferred compounds set forth above can be used in this embodiment.

In another embodiment, the present invention is directed to a method formodulation of CCR-2 receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I). The preferred, particularly preferred, more particularlypreferred, and even more particularly preferred compounds set forthabove can be used in this embodiment.

In another embodiment, the present invention is directed to a method formodulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity,preferably modulation of MCP-1 activity, that is mediated by the CCR2receptor comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I). Thepreferred, particularly preferred, more particularly preferred, and evenmore particularly preferred compounds set forth above can be used inthis embodiment.

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),said disorders being selected from osteoarthritis, aneurysm, fever,cardiovascular effects, Crohn's disease, congestive heart failure,autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis,idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically-or chemically-induced brain trauma, inflammatory bowel disease,alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serumnephritis, glomerularnephritis, asthma, multiple sclerosis,artherosclerosis, rheumatoid arthritis, restinosis, organtransplantation, and cancer; preferably, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis,restinosis, organ transplantation, and cancer; more preferably,alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serumnephritis, glomerularnephritis, asthma, multiple sclerosis,artherosclerosis, and rheumatoid arthritis, restinosis, organtransplantation, and cancer; most preferably asthma, multiple sclerosis,artherosclerosis, rheumatoid arthritis, restinosis, organtransplantation, and cancer. The preferred, particularly preferred, moreparticularly preferred, and even more particularly preferred compoundsset forth above can be used in this embodiment.

In another embodiment, the present invention is directed to a method fortreating inflammatory diseases, preferably, inflammatory diseases whichare at least partially mediated by CCR-2, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I). The preferred, particularly preferred, more particularlypreferred, and even more particularly preferred compounds set forthabove can be used in this embodiment.

In another embodiment, the present invention is directed to a method formodulation of CCR2 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I). The preferred, particularly preferred, more particularly preferred,and even more particularly preferred compounds set forth above can beused in this embodiment.

In another embodiment, the present invention is directed the use of acompound of Formula (I) in the preparation of a medicament for thetreatment of osteoarthritis, aneurysm, fever, cardiovascular effects,Crohn's disease, congestive heart failure, autoimmune diseases,HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.The preferred, particularly preferred, more particularly preferred, andeven more particularly preferred compounds set forth above can be usedin this embodiment.

In another embodiment, the present invention is directed to a compoundof formula (I) for use in therapy. The preferred, particularlypreferred, more particularly preferred, and even more particularlypreferred compounds set forth above can be used in this embodiment.

In another embodiment, the present invention is directed to apharmaceutical composition comprising a compound of formula (I)

or stereoisomers or pharmaceutically acceptable salts thereof, whereinX, Z, a, b, c, d, bond g, n, s, R¹, R², R⁴, R⁵, R¹⁰, R¹², and R¹³, areas defined above, and one or more active ingredients. The preferred,particularly preferred, more particularly preferred, and even moreparticularly preferred compounds set forth above can be used in thisembodiment.

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprised of a compound ofFormula (I) and one or more active ingredients. The preferred,particularly preferred, more particularly preferred, and even moreparticularly preferred compounds set forth above can be used in thisembodiment.

In another embodiment, the present invention is directed to a method formodulation of CCR-2 receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of apharmaceutical composition comprised of a compound of Formula (I) andone or more active ingredients. The preferred, particularly preferred,more particularly preferred, and even more particularly preferredcompounds set forth above can be used in this embodiment.

In yet another embodiment, the present invention is directed to a methodfor modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity,preferably, modulation of MCP-1 activity, that is mediated by the CCR2receptor comprising administering to a patient in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprised of a compound of Formula (I) and one or more activeingredients. The preferred, particularly preferred, more particularlypreferred, and even more particularly preferred compounds set forthabove can be used in this embodiment.

In another embodiment, the present invention is directed to a method fortreating a disorder, comprising administering to a patient in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprised of a compound of Formula (I) and one or moreactive ingredients, wherein said disorder is selected fromosteoarthritis, aneurysm, fever, cardiovascular effects, Crohn'sdisease, congestive heart failure, autoimmune diseases, HIV-infection,HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis,transplant arteriosclerosis, physically- or chemically-induced braintrauma, inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, rheumatoid arthritis, restinosis,organ transplantation, and cancer; preferably, psoriasis, idiopathicpulmonary fibrosis, transplant arteriosclerosis, physically- orchemically-induced brain trauma, inflammatory bowel disease, alveolitis,colitis, systemic lupus erythematosus, nephrotoxic serum nephritis,glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, andrheumatoid arthritis, restinosis, organ transplantation, and cancer;more preferably, alveolitis, colitis, systemic lupus erythematosus,nephrotoxic serum nephritis, glomerularnephritis, asthma, multiplesclerosis, artherosclerosis, and rheumatoid arthritis, restinosis, organtransplantation, and cancer; and most preferably, asthma, multiplesclerosis, artherosclerosis, rheumatoid arthritis; restinosis, organtransplantation, and cancer. The preferred, particularly preferred, moreparticularly preferred, and even more particularly preferred compoundsset forth above can be used in this embodiment.

In yet another embodiment, the present invention, is directed to amethod for treating inflammatory diseases, preferably, inflammatorydiseases which are at least partially mediated by CCR-2, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprised of a compound ofFormula (I) and one or more active ingredients. The preferred,particularly preferred, more particularly preferred, and even moreparticularly preferred compounds set forth above can be used in thisembodiment.

In another embodiment, the present invention is directed to a method formodulation of CCR2 activity comprising-administering to a patient inneed thereof a therapeutically effective amount of a pharmaceuticalcomposition comprised of a compound of Formula (I) and one or moreactive ingredients. The preferred, particularly preferred, moreparticularly preferred, and even more particularly preferred compoundsset forth above can be used in this embodiment.

In another embodiment, the present invention is directed to the use of apharmaceutical composition comprised of a compound of Formula (I) andone or more active ingredients in the preparation of a medicament forthe treatment of osteoarthritis, aneurysm, fever, cardiovasculareffects, Crohn's disease, congestive heart failure, autoimmune diseases,HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.The preferred, particularly preferred, more particularly preferred, andeven more particularly preferred compounds set forth above can be usedin this embodiment.

In still yet another embodiment, the present invention is directed tothe use of a pharmaceutical composition comprised of a compound ofFormula (I) and one or more active ingredients in therapy. Thepreferred, particularly preferred, more particularly preferred, and evenmore particularly preferred compounds set forth above can be used inthis embodiment.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment may be combined with any andall other elements from any of the embodiments to describe additionalembodiments.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such ascamphonic chloride as in Steven D. Young, et al, Antimicrobial Agentsand Chemotheraphy, 1995, 2602-2605.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substitent is keto (i.e., ═O), then 2hydrogens on the atom are replaced.

When any variable (e.g., R¹⁰) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R¹⁰, then saidgroup may optionally be substituted with up to two R¹⁰ groups and R¹⁰ ateach occurrence is selected independently from the definition of R¹⁰.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom, which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term aromatic heterocyclic system- or“heteroaryl”, is intended to mean a stable 5- to 7-membered monocyclicor bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ringwhich consists of carbon atoms and from 1 to 4 heterotams independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,tetrazolyl, and xanthenyl. In another aspect of the invention, examplesof heteroaryls are indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

As used herein, the term “cyclic acetal” or or the phrase when twovariables “join to form a cyclic acetal” is intended to mean thesubstituent —O—CH₂—O—.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit MCP-1or effective to treat or prevent inflammatory disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

Chemokine antagonists can be derived from compounds of formula 1.1, asshown in Schemes 1-6. Thus, compounds of formula 1.5, which contain afour-membered lactam, are derived from compounds of formula 1.1 as shownin Scheme 1. Peptide coupling with the known serine derivative 1.2 andcyclization under Mitsunobu conditions (see G M Salituro and C ATownsend, J. Am. Chem. Soc. 1990, 112, 760) provides a primary amine,which can be conjugated in a variety of ways well known to one skilledin the art (see also Scheme 4 and accompanying text).

Compounds of formula 2.4, which contain a five-membered lactam, aresynthesized as shown in Scheme 2. Peptide coupling with the knownmethionine derivative 2.1, sulfur alkylation, and intramolecular amidealkylation under basic conditions (NaH may also be used, see Freidingeret al., J. Org. Chem. 1982, 47, 104) provides the gamma-lactam 2.3 fromamine 1.1. Removal of the protecting group provides a primary amine,which can be conjugated in a variety of ways well known to one skilledin the art (see also Scheme 4 and accompanying text).

Compounds of formula 3.4, which contain a six-membered lactam, aresynthesized as shown in Scheme 3. Reductive amination with the knownglutamic acid derivative 3.1 (X. Zhang, W. Han, WO PCT 0164678, 2001),ester hydrolysis, and intramolecular amide formation provides thedelta-lactam 3.3 from carbamate 1.1. Removal of the protecting groupprovides a primary amine, which can be conjugated in a variety of wayswell known to one skilled in the art (see also Scheme 4 and accompanyingtext).

Lactams of formula 4.1 can be made from compounds such as 1.4, 2.3, and3.3 (by deprotection and optional reductive amination to install R⁸).Variants of 4.1 with R¹⁰ substituents can be made through synthesesanalogous to those shown in Scheme 1-3 through substitution of theappropriate R¹⁰-substituted starting materials. Derivitization of aminesof formula 4.1 can be accomplished through a number of conventionalmethods to form chemokine receptor antagonists; some of these methodsare illustrated in Scheme 4. Thus, amide bond formation gives compounds4.2, reductive amination gives compounds 4.3, and reaction with anisocyanate gives compounds 4.4. Alternatively, amine 4.1 can be arylated(see D. Zim & S. L. Buchwald, Organic Letters 2003, 5, 2413 and T. Wang,D. R. Magnia, & L. G. Hamann, ibid, 897, and references cited therein)to give compound 4.5. Alternatively, amine 4.1 can be arylated withiminoyl chlorides to give 4.6.

The combination of the chemistry illustrated in Schemes 1-4 can producea large number of chemokine receptor antagonists. Conceptually relatedantagonists can be produced using the chemistry shown in Scheme 5. Thus,reductive amination of 1.1 with aldehyde 5.1 (derived from dimethylmalonate via alkylation and ozonolysis) gives compound 5.2, which can becyclized to 5.3 with base; Hydrolysis of the methyl ester provides anacid which can be coupled with amines to give compounds of interest withformula 5.4. If R² is appropriately functionalized, compounds of formula5.4 can be cyclized to give heterocycles of formula 5.5 (K. Takeuchi etal. Bioorg. Med. Chem. Lett. 2000, 2347; G. Nawwar et al. Collect.Czech. Chem. Commun. 1995, 2200; T. Hisano et al. Chem. Pharm. Bull.1982, 2996). Other heterocycles (see formula 5.6) can be made fromcompounds of formula 5.4 through methods well known to one skilled inthe art (see T. L. Gilchrist, Heterocyclic Chemistry, Longman Scientific& Technical, 1985).

Other chemistry can produce related chemokine antagonists. For example,as shown in Scheme 6, compounds of formula 1.1 are conjugated withcompounds of formula 6.1 in methanol via 1,4-addition. The resultantketone 6.2 may be homologated to 6.3 (isomers are separated viachromatography), which is in turn deprotected and cyclized to givecompounds of interest of formula 6.4.

Although amines of formula 1.1 are shown as unprotected amines, they maysynthesized with the amine in protected form. Also, although amines offormula 1.1 are shown with the cyclic amine bearing a substituent R⁵,they may be synthesized with R⁵ replaced with an appropriate protectinggroup, in which case removal of the protecting group and introduction ofR⁵ in a subsequent step can be achieved, requiring only minoradjustments to the chemistry of Schemes 1 and 2.

The bicyclic diamines 1.1 and protected forms thereof can be preparedusing a variety of methods, such as those described in Schemes 7 and 9(wherein P denotes either an appropriate amine protecting group, or agroup R⁵). One method, shown in Scheme 7, involves conversion of acarboxylic acid (R═OH), acid chloride (R═Cl) or mixed anhydride(R═OC(═O)-alkyl or OC(═O)O-alkyl) 7.1 into an acyl azide 7.2, followedby thermal rearrangement to the isocyanate 7.3, commonly referred to asthe Curtius rearrangement. Treatment of the intermediate isocyanate withwater can provide the amine 7.4 (a protected variant of 1.1) directly.Alternatively, treatment of the intermediate isocyanate with an alcoholsuch as benzyl alcohol can provide the carbamate 7.5, which can bedeprotected to provide 7.4. Some examples of the use of the Curtiusrearrangement to effect transformations analogous to those shown inScheme 7 have been reported by J. Altman and D. Ben-Ishai, TetrahedronAsymmetry 1994, 5,887; K. Ninomiya, T. Shioiri and S. Yamada,Tetrahedron 1974, 30, 2151; L. M. Gustavson and A. Srinivasan, Synth.Commun., 1991, 21, 265; R. Pires and K. Burger, Synthesis 1996, 1277;and E. Neufellner, H. Kapeller and H. Griengl, Tetrahedron 1998, 54,11043.

A related method for achieving the transformation of a carboxylic acidderivative to an amine as shown in Scheme 7 involves treatment of anamide 7.1 (R═NH₂) with an oxidizing agent such as sodium hypobromite orI,I-bis-(trifluoroacetoxy)iodobenzene to provide the amine 7.4, areaction commonly referred to as the Hofmann rearrangement. Thistransformation is reviewed by Wallis and Lane, Org. Reactions 1946, 3,267; a more recent example was reported by Radhakrishna et al., J. Org.Chem. 1979, 44, 1746.

The carboxylic acids and derivatives 7.1 can be prepared using methodswell known in the art of organic synthesis. For example, as shown inScheme 8, a carboxylate ester 8.2 can be prepared by the Diels-Alderreaction of a 3-vinyl-1,4,5,6-tetrahydropyridine 8.1 with an acrylateester, as reported by C. Ludwig and L. G. Wistrand, Acta Chem. Scand.,1989, 43, 676. Also shown in Scheme 8 is another example, involving theintramolecular Diels-Alder reaction of 8.3 to provide the ester 8.4, asreported by S. Wattarasin, F. G. Kathawala and R. K. Boeckman, J. Org.Chem. 1985, 50, 3810.

Another method for the preparation of bicyclic diamines 1.1 andprotected forms thereof, as shown in Scheme 9, is by conversion of aketone such as 9.1 to the oxime or substituted oxime (X′═OH or O-benzyl,for example) 9.2 followed by reduction to an amine 9.3 (R¹²═H) using areducing agent such as lithium aluminum hydride or borane.Alternatively, the oxime or substituted oxime 9.2 can be treated with anorganometallic reagent such as R¹²Li or R¹²MgBr, followed by reductivecleavage of the N—O bond in the cases of oximes or substituted oximes,to provide amines 9.3. This type of transformation is well known in theliterature of organic chemistry. References to some examples are givenin R. C. Larock, Comprehensive Organic Transformations, VCH, 1989.

Ketones 9.1 can also be converted to amines by reductive amination,using well known procedures, to provide amines 9.3 (R¹²═H).

Alternatively, ketones 9.1 can be converted to alcohols 9.4 by reductionusing reagents such as sodium borohydride or lithium aluminum hydride.The alcohols 9.4 can be converted to the primary amines 9.3 (R¹²═H)using several methods, for instance by conversion of the hydroxyl groupto a leaving group such as methanesulfonate, trifluoromethanesulfonateor p-toluenesulfonate; displacement of the leaving group with anappropriate nucleophile such as azide anion; and reduction of theresulting azide to an amine using, for example, a method such ascatalytic hydrogenation or reduction with triphenylphosphine followed byhydrolysis of the intermediate iminophosphorane with water. Examples ofthese transformations can be found in K. Hilpert et al., J. Med. Chem.1994, 37, 3889; C. Lebarbier et al., Synthesis 1996, 1371; and M.Rubiralta et al., Synth. Commun., 1992, 22, 359. The alcohols 9.4 canalso be converted directly to the corresponding azides with reagentssuch as hydrazoic acid or diphenylphosphoryl azide in the presence of adialkyl azodicarboxylate and triphenylphosphine, for example asdescribed in B. Lal et al., Tetrahedron Lett., 1977, 1977; or J. Hieblet al., J. Med. Chem. 1991, 34, 1426.

Ketones 9.1 may be prepared using a wide variety of synthetic methods asreported in the literature of organic chemistry. For example, thecarboxylic acids 7.1 (R═OH) shown in Scheme 7 may be converted to thecorresponding ketones 9.1 using the oxidative decarboxylation methodreported by H. Wasserman and B. H. Lipshutz, Tetrahedron Lett., 1975,4611. Numerous other methods have been reported for preparation of thebicyclic ring systems corresponding to the ketones 9.1, with varioussubstitution on the rings and various protecting groups or substitutionon the ring nitrogen. In some cases, the reported methods can directlyyield the desired ketones 9.1. In other cases, minor modifications ofthe reported methods, which will be obvious to one skilled in the art oforganic synthesis, can yield the desired ketones 9.1. In still othercases, simple synthetic transformations of the reported products,obvious to one skilled in the art, can yield the desired ketones 9.1.Some examples of such methods are listed below.

Ketones 9.1 (a=0; b=0, 1, or 2; c=0; d=3) can be prepared by cyclizationof a 2-(3-aminopropyl)-cyclopentanone derivative followed byhydroboration and oxidation (L. E. Overman, G. M. Robertson, and A. J.Robichaud, J. Amer. Chem. Soc. 1991, 113, 2598; L. E. Overman et al.,Tetrahedron 1981, 37, 4041) or by cyclization of a2-cyano-3-(2-alkoxycarbonylethyl)-piperidine derivative followed by acidhydrolysis and decarboxylation (C. H. Heathcock, M. H. Norman and D. A.Dickman, J. Org. Chem. 1990, 55, 798). Ketones 9.1 (a=0; b=1, 2 or 3;c=1; d=1) can be prepared by reaction of an iminiumylide with a2-cycloalkenone (Eur. Pat. Appl. 0 359 172 A1; M. Ogata et al., Eur. J.Med. Chem. 1991, 26, 889; O. Tsuge et al., Bull. Chem. Soc. Japan 1987,60, 4079; K. Miyajima, M. Takemoto and K. Achiwa, Chem. Pharm. Bull.,1991, 39, 3175). Ketones 9.1 (a=0; b=1; c=1; d=2) can be prepared byhydroboration of a 4-vinyl-1,2,5,6-tetrahydropyridine derivative,followed by reaction with potassium cyanide and oxidation (M. Ogata etal., Eur. J. Med. Chem., 1991, 26, 889).

Ketones 9.1 (a=0; b=2; c=1; d=2) can be prepared by reduction of an8-nitroisoquinoline derivative followed by subsequent syntheticmanipulations (I. W. Mathison and P. H. Morgan, J. Org. Chem. 1974, 39,3210). Ketones 9.1 (a=0; b=1, 2 or 3; c=0; d=2) can be prepared bycyclization of an N-bromo-3-(2-aminoethyl)-cycloalkene derivative (E. J.Corey, C. P. Chen and G. A. Reichard, Tetrahedron Lett., 1989, 30, 5547)or iodine-induced cyclization of a cycloalken-3-ylacetamide derivative(S. Knapp and A. T. Levorse, J. Org. Chem. 1988, 53, 4006) followed bysubsequent synthetic manipulations, or by radical cyclization of a2,2-dichloro-N-(1-oxocycloalk-2-en-2-yl)acetamide, followed bysubsequent synthetic manipulations (A. F. Parsons and D. A. J. Williams,Tetrahedron 2000, 56, 7217).

Ketones 9.1 (a=1; b=0; c=1; d=2) can be prepared by the intramolecularPauson-Khand reaction of an appropriately substituted 4-aza- or5-aza-oct-1-ene-7-yne derivative (G. L. Bolton, J. C. Hodges and J. R.Rubin, Tetrahedron 1997, 53, 6611; B. L. Pagenkopf et al., Synthesis2000, 1009), or by the Schmidt reaction oftetrahydropentalene-2,5(1H,3H)-dione (G. Vidau et al., TetrahedronAsymm. 1997, 8, 2893; V. Gracias et al., Tetrahedron 1997, 53, 16241)followed by subsequent synthetic manipulations. Ketones 9.1 (a=1; b=1;c=1; d=2) can be prepared by the ring-closing metathesis reaction of a3,4-diallylpiperidine derivative followed by hydroxylation of theresulting 1,2,3,4,4a,5,8,8a-octahydroisoquinoline (S. Liras, M. P. Allenand J. F. Blake, Org. Lett., 2001, 3, 3483).

Ketones 9.1 (a=1; b=0; c=0; d=2) can be prepared by Dieckmanncyclization of an appropriate dialkyl 2,2′-pyrrolidine-2,3-diyldiacetatederivative (C. L. J. Wang, Tetrahedron Lett., 1983, 24, 477) or bycyclization of the acyliminium ion derived from an appropriate3-{2-[(trialkylsilyl)methyl]prop-2-en-1-yl}pyrrolidin-2-one derivative(J. C. Gramain and P. Remuson, Heterocycles 1989, 29, 1263). Ketones 9.1(a=1; b=1; c=0; d=2 or 3) can be prepared by dissolving metal reductionof an appropriate 4-alkoxyphenethylamine or 4-alkoxyphenpropylaminederivative, followed by hydrolysis and cyclization (J. Bonjoch et al.,Tetrahedron Asymm., 1997, 8, 3143; U.S. Pat. No. 4,600,777; T. Momose etal., Chem. Pharm. Bull., 1977, 25, 1797) or by dissolving metalreduction of an appropriate 6-alkoxyindoline derivative followed byhydrolysis and double bond reduction (H. Iida, Y. Yuasa and C.Kibayashi, J. Org. Chem., 1979, 44, 1074).

Ketones 9.1 (a=1; b=1; c=0; d=3) can be prepared by cyclization of anappropriate 3-(4-oxocyclohex-2-en-1-yl)propanamide followed by amidereduction (A. I. Meyers and D. Berney, J. Org. Chem. 1989, 54, 4673) orby reaction of but-3-en-2-one with an appropriate1,4,5,6-tetrahydropyridine derivative (E. Vazquez et al., TetrahedronAsymm., 2001, 12, 2099). Ketones 9.1 wherein a=0 can, in general, betransformed into ketones 9.1 wherein a=1 by means of 1,2-carbonyltransposition methods, such as those described by M. Ogata et al., Eur.J. Med. Chem. 1991, 26, 889; W. E. Fristad, T. R. Bailey and L. A.Paquette, J. Org. Chem. 1978, 43, 1620; J. A. Marshall and H. Roebke, J.Org. Chem. 1969, 34, 4188; Y. Tsuda ad S. Hosoi, Chem. Pharm. Bull.1985, 33, 1745; and T. Nakai and T. Mimura, Tetrahedron Lett. 1979, 531.

When these methods are considered, it is apparent that a large number ofcompounds of formula 1.1 can be synthesized.

The present invention is now described in more detail by reference tothe following examples, but it should be understood that the inventionis not construed as being limited thereto.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “° C.” fordegrees Celsius, “g” for gram or grams, “mg” for milligram ormilligrams, “mL” for milliliter or milliliters, “mmol” for millimole ormillimoles, “μL” for microliter or microliters, “μmol” for micromole ormicromoles, “h” for hour or hours, “M” for molar, “N” for normal, “min”for minute or minutes, “MS” for mass spectroscopy, “ES+” for positiveelectrospray ionization, “m/z” for molecular weight divided by charge,“RT” for room temperature, “CH₂Cl₂” for methylene chloride, “DMF” fordimethylformamide, “TBTU” forO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,“brine” for an aqueous saturated sodium chloride solution, “MeOH” formethanol, “HPLC” for high performance liquid chromatography.

Example 1 Part A: Preparation ofendo-5-benzylaminooctahydro-cyclopenta[c]pyrrole-2-carboxylic acidtert-butyl ester

5-Oxooctahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester(prepared in the manner described by D. P. Becker and D. L. Flynn,Tetrahedron, 1993, 49, 5047; 500 mg) and benzylamine (242 μL) weredissolved in 1,2-dichloroethane (8 mL). Acetic acid (190 μL) and sodiumtriacetoxyborohydride (706 mg) were added sequentially, and the mixturewas stirred at room temperature for 2.75 h. Aqueous sodium hydroxide(1.0 N) was added and the mixture was stirred rapidly for a few minutes.The layers were separated, and the aqueous phase was extracted withdichloromethane. The combined organic phases were dried over sodiumsulfate and concentrated under vacuum to yield a residue. The residuewas purified by flash chromatography to provide the title compound as apale yellow oil (538 mg). MS (ES⁺) m/z 317.21 (M+H⁺). Also isolated wasa mixture of the title product and its exo-isomer (91 mg).

Part B: Preparation ofendo-5-aminooctahydrocyclo-penta[c]pyrrole-2-carboxylic acid tert-butylester

A mixture ofendo-5-benzylaminooctahydrocyclo-penta[c]pyrrole-2-carboxylic acidtert-butyl ester (525 mg) and 20% palladium hydroxide on carbon(Pearlman's catalyst; 475 mg) in methanol (8 mL) was stirred rapidlyunder 1 atm of hydrogen at room temperature for 17.5 h. The mixture wasfiltered through celite and the solids were washed with methanol. Thecombined filtrates were concentrated to provide a white waxy solid (345mg). MS (ES⁺) m/z 227.18 (M+H⁺).

Part C: Preparation ofendo-5-(2-benzyloxycarbonyl-amino-4-methylsulfanylbutyrylamino)octahydrocyclopenta-[c]pyrrole-2-carboxylicacid tert-butyl ester

Endo-5-amino-octahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butylester is dissolved in 1:1 CH₂Cl₂/DMF. The resultant solution is treatedwith N-benzyloxycarbonyl methionine, N,N-diethylisopropylamine and TBTU.The reaction mixture is stirred at room temperature until completion andthen partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic phases are washed with brine, dried over sodiumsulfate, and concentrated under vacuum yielding a residue. The residueis purified by flash column chromatography providing the title compound.

Part D: Preparation ofendo-5-(3-benzyloxycarbonyl-amino-2-oxopyrrolidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

Endo-5-(2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is dissolved in iodomethane, and the resultingsolution is stirred at RT for 48 h. After this time, the solution isconcentrated in vacuo yielding a residue. The residue is dissolved inmethylene chloride, and the resulting solution is concentrated; this isrepeated to afford the salt. This material is dissolved in DMF and theresulting solution is treated with cesium carbonate and stirred at RTbefore being partitioned between ethyl acetate and brine. The organicphase is dried over sodium sulfate and concentrated under vacuumyielding a residue. The residue is purified by flash columnchromatography providing the title product.

Part E: Preparation ofendo-5-(3-amino-2-oxopyrrolidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A solution ofendo-5-(3-benzyloxycarbonyl-amino-2-oxopyrrolidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester in MeOH is treated with 20% palladium hydroxide oncarbon (Pearlman's catalyst) and stirred under hydrogen (1 atmosphere)until the reaction is complete. The reaction mixture is filtered andthen concentrated under vacuum providing the title product.

Part F: Preparation ofendo-5-[2-Oxo-3-(3-trifluoro-methylbenzoylamino)pyrrolidin-1-yl]octahydro-cyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester

A solution ofendo-5-(3-amino-2-oxopyrrolidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester in DMF is treated with 3-trifluoromethyl-benzoicacid, N,N-diethylisopropylamine and TBTU. The reaction is stirred atroom temperature until completion, and then partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic phases arecombined, washed with brine, dried over sodium sulfate and concentratedin vacuo providing the title product.

Part G: Preparation of the trifluoroacetic acid salt ofendo-N-[1-(octahydrocyclo-penta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoro-methylbenzamide

A solution ofendo-5-[2-Oxo-3-(3-trifluoromethyl-benzoylamino)pyrrolidin-1-yl]octahydrocyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester in dichloromethane is treated with trifluoroaceticacid and stirred at room temperature until the reaction is complete. Thesolution is concentrated under vacuum providing the title product.

Example 2 Preparation of the trifluoroacetic acid salt ofendo-N-[1-(2-isopropyloctahydrocyclo-penta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoro-methylbenzamide

The product of Example 1 is converted to the free base by partitioningbetween ethyl acetate and 1.0 N aqueous sodium hydroxide. The organicphase is dried over sodium sulfate and concentrated yielding a material.This material is dissolved in 1,2-dichloroethane. The resulting solutionis treated sequentially with acetone, acetic acid and sodiumtriacetoxyborohydride. The resulting mixture is stirred at roomtemperature until the reaction is complete, and then concentrated undervacuum yielding a residue. The residue is partitioned between ethylacetate and saturated aqueous sodium hydrogen carbonate. The combinedorganic phases are dried over sodium sulfate and concentrated undervacuum yielding a residue. The residue is purified by reverse phase HPLCand lyophilization providing the title product.

Example 3 Part A: Preparation of allyl-hex-2-ynyl-carbamic acidtert-butyl ester

A solution of allyl-prop-2-ynyl-carbamic acid tert-butyl ester (preparedin the manner described by Boger et al., J. Am. Chem. Soc., 1996, 118,2109; 1.95 g) in anhydrous tetrahydrofuran (10 mL) was stirred at 0° C.in a cooling bath and treated with n-butyllithium (1.6 M solution inhexane; 7.2 mL) during a 5 min period. After being stirred for anadditional 5 min, the solution was treated sequentially withhexamethylphosphoramide (2 mL) and a solution of 1-iodopropane (1.71 mL)in tetrahydrofuran (2 mL). After 65 min, the cooling bath was removedand the mixture was allowed to warm to room temperature where it stirredfor 80 min. At the conclusion of this period, saturated aqueous ammoniumchloride was added, followed by water to dissolve the solids. Themixture was extracted with ethyl acetate, and the combined organicphases were washed with saturated aqueous sodium chloride, dried oversodium sulfate and concentrated to yield a residue. The residue waspurified by flash chromatography to provide a pale yellowish oil (1.67g). MS (ES⁺) m/z 238.27 (M+H⁺).

Part B: Preparation of5-oxo-6-propyl-3,3a,4,5-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A solution of allyl-hex-2-ynyl-carbamic acid tert-butyl ester (741 mg)in dichloromethane (50 mL) was added to dicobalt octacarbonyl (1.12 g)under an argon atmosphere. The resulting solution was stirred at roomtemperature for 1.5 h. After this time, N-methylmorpholine N-oxide (2.56g) was added in portions during a 60 min period. Upon completion ofaddition, the reaction mixture was stirred for an additional 2.5 h. Atthe conclusion of this period, the mixture was filtered through silicagel, and the solid was washed with a 1:1 ethyl acetate-hexane solution(200 mL). The filtrate was concentrated under vacuum to yield a residue.The residue was purified by flash column chromatography to provide thetitle compound as a light brown oil (321 mg). MS (ES⁺) m/z 266.19(M+H⁺).

Part C: Preparation ofendo-5-oxo-4-propyl-octahydro-cyclopenta[c]pyrrole-2-carboxylic acidtert-butyl ester

A mixture of5-oxo-6-propyl-3,3a,4,5-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester (310 mg), 95% ethanol (6 mL) and 10% palladium oncharcoal (160 mg) was stirred vigorously under 1 atm of hydrogen at roomtemperature for 3.5 h. The mixture was filtered through celite and thesolids were washed with ethanol. The combined filtrates wereconcentrated to provide an oil which was purified by flashchromatography to provide the exo isomer as an oil (11 mg), followed bya mixture of both isomers (ca. 15:85 exo:endo, 105 mg), and the endoisomer (135 mg) (endo:exo ca. 9:1 overall). Endo isomer: MS (ES⁺) m/z368.21 (M+H⁺). Exo isomer: MS (ES⁺) m/z 368.21 (M+H⁺).

Part D: Preparation of4-endo-5-benzylamino-4-propyl-octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A solution ofendo-5-oxo-4-propyloctahydro-cyclopenta[c]pyrrole-2-carboxylic acidtert-butyl ester (264 mg) in 1,2-dichloroethane (4 mL) was treatedsequentially with benzylamine (108 μL), acetic acid (85 μL) and sodiumtriacetoxyborohydride (314 mg). The reaction mixture was stirred at roomtemperature for 70 h, and then analyzed by thin layer chromatography,which indicated that some starting material remained. Additionalquantities of the reagents as given above were added, and the mixturewas stirred for an additional 64 h. After this period, the mixture wasconcentrated under vacuum to yield a residue. The residue waspartitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted twice more with ethylacetate, and the combined extracts were dried over sodium sulfate andconcentrated under vacuum to yield a residue. The residue was purifiedby flash column chromatography to yield the title compound as an oil(184 mg), which was a mixture of exo and endo amine isomers. MS (ES⁺)m/z 355 (M+H⁺).

Part E: Preparation of4-endo-5-amino-4-propyl-octahydrocyclopenta[c]pyrrole-2-carboxylic acidtert-butyl ester

A solution of4-endo-5-benzylamino-4-propyl-octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester (200 mg) in methanol (5 mL) was stirred with 20%palladium hydroxide on charcoal (Pearlman's catalyst; 200 mg) under 1atm of hydrogen for 18 h. At the conclusion of this period, the mixturewas filtered through celite, and the solids were washed with methanol.The filtrate was concentrated to provide the title compound as a glassyfoam (154 mg) which was a mixture of diastereomers (ca. 7:3). MS (ES⁺)m/z 269.25 (M+H⁺).

Part F: Preparation of4-endo-N-[1-(2-isopropyl-4-propyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoromethyl-benzamide

Following the procedures of Example 1, Parts C through G, followed bythe procedure of Example 2,4-endo-5-amino-4-propyloctahydrocyclopenta[c]pyrrole-2-carboxylic acidtert-butyl ester is converted to the title product.

Example 4 Part A: Preparation of4-endo-5-(3-amino-2-oxopyrrolidin-1-yl)-4-propyloctahydrocyclopenta-[c]pyrrole-2-carboxylicacid tert-butyl ester

Following the procedures of Example 1, Parts C through E,4-endo-5-amino-4-propyloctahydrocyclopenta-[c]pyrrole-2-carboxylic acidtert-butyl ester is converted to the title compound.

Part B: Preparation of4-endo-5-{3-[2-(3-isopropylureido)-5-trifluoromethyl-benzoylamino]-2-oxopyrrolidin-1-yl}-4-propyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

Following the procedure of Example 1, Part F, but using2-(3-isopropylureido)-5-trifluoromethylbenzoic acid (see WO-02/50019)rather than 3-trifluoromethyl-benzoic acid,4-endo-5-(3-amino-2-oxopyrrolidin-1-yl)-4-propyloctahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is converted to the title compound.

Part C: Preparation of4-endo-N-[1-(2-isopropyl-4-propyl-octahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-2-(3-isopropylureido)-5-trifluoromethylbenzamide

Following the procedure of Example 1, Part G, and then that of Example2,4-endo-5-{3-[2-(3-isopropylureido)-5-trifluoromethyl-benzoylamino]-2-oxopyrrolidin-1-yl}-4-propyloctahydrocyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester is converted to the title product.

Example 5 Part A. Preparation of acetic acid4-(tert-butoxy-carbonylprop-2-ynylamino)-but-2-enyl ester

Following the procedure described in Boger et al. (J. Am. Chem. Soc.,1996, 118, 2109) but using acetic acid 4-chlorobut-2-enyl ester (seeOrgan et al., J. Org. Chem. 2000, 65, 7959 ) rather than allyl bromide,prop-2-ynylcarbamic acid tert-butyl ester is converted to the titleproduct.

Part B. Preparation of4-acetoxymethyl-5-(3-benzyloxy-carbonylamino-2-oxopyrrolidin-1-yl)-octahydrocyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester

By sequentially following the procedures of Example 3, Parts B and C,and Example 1, Parts A through D, acetic acid4-(tert-butoxy-carbonylprop-2-ynylamino)-but-2-enyl ester is convertedto the title product.

Part C. Preparation of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-hydroxymethyloctahydro-cyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester

A solution of4-acetoxymethyl-5-(3-benzyloxycarbonyl-amino-2-oxopyrrolidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester in tetrahydrofuran is treated with aqueous lithiumhydroxide. The reaction mixture is stirred at room temperature until thereaction is complete. Upon completion of the reaction, the reactionmixture is concentrated under vacuum yielding an aqueous residue. Theaqueous residue is extracted with ethyl acetate. The organic phases aredried over sodium sulfate and concentrated under vacuum yielding aresidue. The residue is purified by flash column chromatographyproviding the title product.

Part D. Preparation of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-methoxymethyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A solution of5-(3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-4-hydroxymethyloctahydrocyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester in a small amount of DMF and a large excess ofiodomethane is treated with silver oxide and stirred at room temperatureuntil the reaction is complete. Upon completion of the reaction, thereaction mixture is filtered through celite and concentrated undervacuum yielding a residue. The residue is purified by flash columnchromatography providing the title product.

Part E. Preparation of5-(3-amino-2-oxopyrrolidin-1-yl)-4-methoxymethyloctahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

Following the procedure of Example 1, Part E,5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-methoxy-methyloctahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is converted to the title product.

Part F. Preparation ofN-[1-(2-isopropyl-4-methoxy-methyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoromethylbenzamide

By sequentially following the procedures of Example 1, Parts F and G,and Example 2,5-(3-amino-2-oxopyrrolidin-1-yl)-4-methoxymethyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is converted to the title product.

Example 6 Part A. Preparation of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-isopropylsulfanylmethyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A solution of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-hydroxymethyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester (see Example 5, Part C) in dichloromethane iscooled to 0° C. and treated with triethylamine and methanesulfonylchloride. Upon completion of addition, the reaction mixture is allowedto warm to room temperature where it is stirred until the reaction iscomplete. Upon completion of the reaction, water is added. The aqueousphase is extracted with ethyl acetate and concentrated yielding amethanesulfonate material. In a separate flask, propane-2-thiol isdissolved in DMF and cooled to 0° C. Once at the prescribed temperature,sodium hydride is added. Upon completion of addition, the reactionmixture is allowed to warm to room temperature where it is stirred for 2h. After this time, the methanesulfonate material prepared above isdissolved in DMF and added slowly to the thiolate solution. Theresulting mixture is stirred until the reaction is complete. Water andethyl acetate are added. The organic phase is dried over sodium sulfateand concentrated yielding a residue. The residue is purified by flashcolumn chromatography providing the title product.

Part B. Preparation of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-(propane-2-sulfonylmethyl)-octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A solution of5-(3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-4-isopropylsulfanylmethyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester in isopropanol is treated with a solution of oxonein water. The reaction mixture is stirred at room temperature until thereaction is complete, and then water and ethyl acetate are added. Theorganic layer is separated, dried over sodium sulfate and concentratedunder vacuum providing the title product.

Part C. Preparation ofN-{1-[2-isopropyl-4-(propane-2-sulfonylmethyl)octahydrocyclopenta[c]pyrrol-5-yl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethylbenzamide

By sequentially following the procedures of Example 1, Parts E throughG, and Example 2,5-(3-benzyloxy-carbonylamino-2-oxopyrrolidin-1-yl)-4-(propane-2-sulfonylmethyl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is converted to the title product.

Example 7 Part A. Preparation of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-phenylsulfanylmethyloctahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

A mixture of5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-hydroxymethyloctahydro-cyclopenta[c]-pyrrole-2-carboxylicacid tert-butyl ester (see Example 5, Part C), diphenyl disulfide,tributylphosphine and tetrahydrofuran is heated at reflux until thereaction is complete. The reaction mixture is then cooled to roomtemperature and concentrated yielding a residue. The residue is purifiedby flash column chromatography providing the title product.

Part B. Preparation of4-benzenesulfonylmethyl-5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)octahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester

Following the procedure of Example 6, Part B,5-(3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-4-phenyl-sulfanylmethyloctahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is converted to the title product.

Part C. Preparation ofN-[1-(4-benzenesulfonyl-methyl-2-isopropyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxo-pyrrolidin-3-yl]-3-trifluoromethylbenzamide

By sequentially following the procedures of Example 1, Parts E throughG, and Example 2,4-benzenesulfonyl-methyl-5-(3-benzyloxy-carbonylamino-2-oxopyrrolidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester is converted to the title product.

Example 8 Part A. Preparation of[1-(2-isopropyl-4-methoxy-methyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester

By sequentially following the procedures of Example 1, Part G, andExample 2,5-(3-amino-2-oxopyrrolidin-1-yl)-4-methoxymethyloctahydrocyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester (see Example 5, Part E) is converted to the titleproduct.

Part B. Preparation of3-amino-1-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)-pyrrolidin-2-one

Following the procedure of Example 1, Part E,[1-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]carbamicacid benzyl ester is converted to the title product.

Part C. Preparation of1-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)-3-(6-trifluoromethylquinazolin-4-ylamino)pyrrolidin-2-one

A mixture of3-amino-1-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)-pyrrolidin-2-one,4-chloro-6-trifluoromethylquinazoline (see Armarego et al., J. Chem.Soc. B, 1967, 449) and triethylamine in ethanol is heated at refluxuntil the reaction is complete. The resulting solution is concentratedunder vacuum yielding a residue. The residue is purified by reversephase HPLC and lyophilization providing the title product.

Table of Examples

Representative compounds which can be prepared by the methods discribedabove are listed in Table 1. The substituents listed in the table are tobe paired with the structure embedded in the table heading.

TABLE 1

Example R¹ R⁵ Z R² 1 H H —NHC(═O) 3-CF₃—C₆H₄ 2 H i-Pr —NHC(═O)3-CF₃—C₆H₄ 3 n-Pr i-Pr —NHC(═O) 3-CF₃—C₆H₄ 4 n-Pr i-Pr —NHC(═O)2-(NHC(═O)NH-i-Pr)-5-CF₃—C₆H₃ 5 CH₂OMe i-Pr —NHC(═O) 3-CF₃—C₆H₄ 6CH₂SO₂i-Pr i-Pr —NHC(═O) 3-CF₃—C₆H₄ 7 CH₂SO₂Ph i-Pr —NHC(═O) 3-CF₃—C₆H₄8 CH₂OMe i-Pr —NH— 6-CF₃-4-quinazolinyl

Utility

It is believed that the compounds of formula I are modulators ofchemokine receptor activity. This could be demonstrated using assaysknow by those skilled in the art. In this section, we describe theseassays and give their literature reference. Since it is believed thatthe compounds of formula I would display activity in these assays ofMCP-1 antagonism, it is believed that the compounds of formula I wouldbe useful in the treatment of human diseases associated with chemokinesand their cognate receptors. The definition of activity in these assayswould be a compound demonstrating an IC₅₀ of 20 μM or lower inconcentration when measured in a particular assay.

Antagonism of MCP-1 Binding to Human PBMC

(Yoshimura et al., J. Immunol., 1990, 145, 292)

Compounds of the present invention are believed to have activity in theantagonism of MCP-1 binding to human PBMC (human peripheral bloodmononuclear cells) described here.

Millipore filter plates (#MABVN1250) are treated with 100 μl of bindingbuffer (0.5% bovine serum albumin, 20 mM HEPES buffer and 5 mM magnesiumchloride in RPMI 1640 media) for thirty minutes at room temperature. Tomeasure binding, 50 μl of binding buffer, with or without a knownconcentration compound, is combined with 50 μl of ¹²⁵-I labeled humanMCP-1 (to give a final concentration of 150 pM radioligand) and 50 μl ofbinding buffer containing 5×10⁵ cells. Cells used for such bindingassays can include human peripheral blood mononuclear cells isolated byFicoll-Hypaque gradient centrifugation, human monocytes (Weiner et al.,J. Immunol. Methods, 1980, 36, 89), or the THP-1 cell line whichexpresses the endogenous receptor. The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and the plates washedthree times with binding buffer containing 0.5M NaCl. The plastic skirtis removed from the plate, the plate allowed to air dry, the wellspunched out and counted. The percent inhibition of binding is calculatedusing the total counts obtained in the absence of any competing compoundand the background binding determined by addition of 100 nM MCP-1 inplace of the test compound.

Antagonism of MCP-1-induced Calcium Influx

(Sullivan et al., Methods Mol. Biol., 114, 125-133 (1999)

Compounds of the present invention are believed to have activity in theantagonism of MCP-1-induced calcium influx assay described here.

Calcium mobilization is measured using the fluorescent Ca²⁺ indicatordye, Fluo-3. Cells are incubated at 8×10⁵ cells/ml in phosphate-bufferedsaline containing 0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mMglucose, 1% fetal bovine serum, 4 μM Fluo-3 AM and 2.5 mM probenecid for60 minutes at 37° C. Cells used for such calcium assays can includehuman monocytes isolated as described by Weiner et al., J. Immunol.Methods, 36, 89-97 (1980) or cell lines which expresses the endogenousCCR2 receptor such as THP-1 and MonoMac-6. The cells are then washedthree times in phosphate-buffered saline containing 0.1% bovine serumalbumin, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid. The cells areresuspended in phosphate-buffered saline containing 0.5% bovine serumalbumin, 20 mM HEPES and 2.5 mM probenecid at a final concentration of2-4×10⁶ cells/ml. Cells are plated into 96-well, black-wall microplates(100 μl/well) and the plates centrifuged at 200×g for 5 minutes. Variousconcentrations of compound are added to the wells (50 μl/well) and after5 minutes, 50 μl/well of MCP-1 is added to give a final concentration of10 nM. Calcium mobilization is detected by using a fluorescent-imagingplate reader. The cell monolayer is excited with an argon laser (488 nM)and cell-associated fluorescence measured for 3 minutes, (every secondfor the first 90 seconds and every 10 seconds for the next 90 seconds).Data are generated as arbitrary fluorescence units and the change influorescence for each well determined as the maximum-minimumdifferential. Compound-dependent inhibition is calculated relative tothe response of MCP-1 alone.

Antagonism of MCP-1-induced Human PBMC Chemotaxis

(Bacon et al., Brit. J. Pharmacol., 1988, 95, 966)

Compounds of the present invention are believed to have activity in theantagonism of MCP-1-induced human PBMC chemotaxis assay described here.

Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics MPC 96 wellplate, and Neuroprobe polyvinylpyrrolidone-free polycarbonate PFD58-micron filters are warmed in a 37° C. incubator. Human PeripheralBlood Mononuclear Cells (PBMCs) (Boyum et al., Scand. J. Clin. LabInvest. Suppl., 1968, 97, 31), freshly isolated via the standard ficolldensity separation method, are suspended in DMEM at 1×10 ⁷ c/ml andwarmed at 37° C. A 60 nM solution of human MCP-1 is also warmed at 37°C. Dilutions of test compounds are made up at 2× the concentrationneeded in DMEM. The PBMC suspension and the 60 nm MCP-1 solution aremixed 1:1 in polypropylene tubes with prewarmed DMEM with or without adilution of the test compounds. These mixtures are warmed in a 37° C.tube warmer. To start the assay, add the MCP-1/compound mixture into thewells of the Polyfiltronics MPC 96 well plate that has been placed intothe bottom part of the Neuroprobe chemotaxis chamber. The approximatevolume is 400 μl to each well and there should be a positive meniscusafter dispensing. The 8 micron filter is placed gently on top of the 96well plate, a rubber gasket is attached to the bottom of the upperchamber, and the chamber is assembled. A 200 μl volume of the cellsuspension/compound mixture is added to the appropriate wells of theupper chamber. The upper chamber is covered with a plate sealer, and theassembled unit is placed in a 37° C. incubator for 45 minutes. Afterincubation, the plate sealer is removed and all the remaining cellsuspension is aspirated off. The chamber is disassembled and the filtergently removed. While holding the filter at a 90-degree angle,unmigrated cells are washed away using a gentle stream of phosphatebuffered saline and the top of the filter wiped with the tip of a rubbersqueegee. Repeat this wash twice more. The filter is air dried and thenimmersed completely in Wright Geimsa stain for 45 seconds. The filter isthen washed by soaking in distilled water for 7 minutes, and then a 15second additional wash in fresh distilled water. The filter is againair-dried. Migrated cells on the filter are quantified by visualmicroscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.

Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematological malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases.

In addition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for promoters of chemokinereceptor function if one contemplates the delivery of sufficientcompound to cause the loss of receptor expression on cells through theinduction of chemokine receptor internalization or delivery of compoundin a manner that results in the misdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

The compounds of the present invention may be used to treat or preventdisorders selected from rheumatoid arthritis, osteoarthritis, septicshock, atherosclerosis, aneurysm, fever, cardiovascular effects,haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,malaria, Crohn's disease, inflammatory bowel diseases, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, autoimmune diseases, skininflammatory diseases, multiple sclerosis, radiation damage, hyperoxicalveolar injury, HIV, HIV dementia, non-insulin dependent diabetesmelitus, asthma, allergic rhinitis, atopic dermatitis, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, cystic fibrosis, Churg-Strauss syndrome, lymphoma,Hodgkin's disease, colonic carcinoma, Felty's syndrome, sarcoidosis,uveitis, Alzheimer, Glomerulonephritis, and systemic lupuserythematosus.

In another aspect, the compounds may be used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, aneurysm, fever, cardiovasculareffects, Crohn's disease, inflammatory bowel diseases, psoriasis,congestive heart failure, multiple sclerosis, autoimmune diseases, skininflammatory diseases.

In another aspect, the compounds may be used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, Crohn's disease, inflammatory boweldiseases, and multiple sclerosis.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention may be used. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) integrin antagonists such as those for selectins, ICAMs and VLA-4;(b) steroids such as beclomethasone, methylprednisolone, betamethasone,prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressantssuch as cyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal anti-inflammatory agents(NSAIDs) such as propionic acid derivatives (alminoprofen, benxaprofen,bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (l) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,anti-metabolites such as azathioprine and 6-mercaptopurine, andcytotoxic cancer chemotherapeutic agents. The weight ratio of thecompound of the present invention to the second active ingredient may bevaried and will depend upon the effective doses of each ingredient.

Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, or alternatively fromabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, or between about 0.01 to 100mg/kg of body weight per day, or alternatively, between about 1.0 to 20mg/kg/day. Intravenously, the doses will range from about 1 to about 10mg/kg/minute during a constant rate infusion. Compounds of thisinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three, or four timesdaily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Dosage forms(pharmaceutical compositions) suitable for administration may containfrom about 1 milligram to about 100 milligrams of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration may contain a water soluble saltof the active ingredient, suitable stabilizing agents, and if necessary,buffer substances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Representative useful pharmaceutical dosage-formsfor administration of the compounds of this invention can be illustratedas follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The. capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin. Where the compoundsof this invention are combined with other anticoagulant agents, forexample, a daily dosage may be about 0.1 to 100 milligrams of thecompound of Formula I and about 1 to 7.5 milligrams of the secondanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the compounds of this invention generally may be present in anamount of about 5 to 10 milligrams per dosage unit, and the secondanti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination. Particularly when provided as asingle dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a lowviscosity grade of hydroxypropylmethylcellulose (HPMC) or other appropriate materials as known in theart, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

1. A compound of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: X is selected from O or S; Z is selected from a bond,—C(O)NR⁸—, —NR⁹—, —NR⁹—CR¹⁴R¹⁴—, —NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—,—NR⁸C(S)NH—, —NR⁸SO₂—, —NR⁸SO₂NH—, —OC(O)NR⁸—, —NR⁸C(O)O—,—(CR²⁵R²⁵)_(u)—, —CR¹⁴═CR¹⁴—, —CR²⁵R²⁵C(O)—, —C(O)CR²⁵R²⁵,—CR²⁵R²⁵C(═N—OR¹⁴)—, —O—CR¹⁴R¹⁴—, —CR¹⁴R¹⁴—O—, —CR¹⁴R¹⁴—NR⁹—,—S(O)_(p)—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—;wherein neither Z nor R¹³ is connected to a carbon atom to which R¹⁰ isattached; bond (g) is a single or double bond; alternatively, when n isequal to 2, the two carbon atoms may join through a double bond; R¹ isselected from H, R⁶, C₁₋₆ alkyl substituted with 0-3 R⁶, C₂₋₆ alkenylsubstituted with 0-3 R⁶, C₂₋₆ alkynyl substituted with 0-3 R⁶, C₆₋₁₀aryl group substituted with 0-5 R⁶, and a 5-10 membered heteroarylsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5R⁷ and a 5-10 membered heteroaryl containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-3 R⁷; R⁴ is absent, taken with thenitrogen to which it is attached to form an N-oxide, or selected fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,(CR′R′)_(q)C(O)R^(4b), (CR′R′)_(q)C(O)NR^(4a)R^(4a),(CR′R′)_(q)C(O)OR^(4b), and a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(4c); R^(4a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,and phenyl; alternatively, two R^(4a)s, together with the N to whichthey are attached, join to form a 3-8 membered heterocycle containing0-1 additional heteroatoms selected from N, O and S; R^(4b), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CR′R′)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl; R^(4c), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CR′R′)_(r)OC₁₋₅ alkyl, (CR′R′)_(r)OH, (CR′R′)_(r)SC₁₋₅ alkyl,(CR′R′)_(r)NR^(4a)R^(4a), and (CR′R′)_(r)phenyl; R⁵ is selected from H,C₁₋₆ alkyl substituted with 0-2 R^(5e), —C(O)R^(5b), —C(O)OR^(5b),—C(O)NR^(5f)R^(5f), a C₃₋₁₀ carbocyclic residue substituted with 0-5R^(5e), and a 5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e);R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CR′R′)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(5e), and a (CR′R′)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(5e); R^(5e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, OH, SH, (CR′R′)_(r)SC₁₋₅alkyl, (CR′R′)_(r)NR^(5f)R^(5f), a (CR′R′)_(r)C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(6e); R^(5f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; alternatively, two R^(5f)s, together withthe N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O andS; R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6a),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a), (CR′R′)_(r)S(O)2NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6a), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); alternatively, two R⁶s onadjacent atoms on may join to form a cyclic acetal; R^(6a), at eachoccurrence, is selected from H, methyl, C₂₋₆ alkyl substituted with 0-2R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynylsubstituted with 0-2 R^(6e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(6e), and a (CR′R′)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(6e); alternatively, two R^(6a)s, togetherwith the N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O,and S; R^(6d), at each occurrence, is selected from C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e),methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₂₋₄ haloalkyl, a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and a(CR′R′)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(6e); R^(6e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CR′R′)_(r)OC₁₋₅ alkyl, OH, SH, (CR′R′)_(r)SC₁₋₅ alkyl,(CR′R′)_(r)NR^(6f)R^(6f) and (CR′R′)_(r)phenyl; R^(6f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, andphenyl; alternatively, two R^(6f)s, together with the N to which theyare attached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R⁷, at each occurrence,is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O) (CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),(CR′R′)_(r)NHC(NR^(7f))═NR^(7f)R^(7f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a(CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); alternatively,two R⁷s on adjacent atoms on R² may join to form a cyclic acetal;R^(7a), at each occurrence, is independently selected from H, methylsubstituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with0-2 R^(7e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(7e), and a (CR′R′)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);alternatively, two R^(7a)s, together with the N to which they areattached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(7e),C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with0-2 R^(7e), a (CR′R′)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(7e), and a (CR′R′)_(r)-4-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl substitutedwith 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃,C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3 R^(7e), a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a(CR′R′)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CR′R′)_(r)cyclopropyl, Cl, F, Br, CN, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅alkyl, OH, C(O)OC₁₋₅ alkyl, (CR′R′)_(r)NR^(7f)R^(7f), and acetyl;R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl, and phenyl; alternatively, two R^(7f)l s, together with theN to which they are attached, join to form a 3-8 membered heterocyclecontaining 0-1 additional heteroatoms selected from N, O and S; R^(7g)is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CR′R′)_(r)phenyl; R′, at each occurrence, is independently, selected from H, methyl, and C₂₋₆ alkyl; alternatively, twoR′s, along with the carbon atom to which they are attached, join to forma cyclopropyl ring; R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄cycloalkyl; R9 is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H,and —C(O)—C₁₋₄ alkyl; R¹⁰ is independently selected from H and C₁₋₄alkyl substituted with 0-1 R^(10b), R^(10b), at each occurrence, isindependently selected from —OH, —SH, —NR^(c)R^(10c),—C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; alternatively, two R^(10c)s, togetherwith the N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O andS; R¹² is selected from H and C₁₋₄ alkyl; R¹³, at each occurrence, isindependently selected from H, —OH, —NH₂, F, Cl, Br, I, —OR^(13a),—N(R^(13a))₂, and C₁₋₄ alkyl substituted with 0-3 R^(13b); R^(13a) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R^(13b), at eachoccurrence, is independently selected from —OH, —SH, —NR^(13c)R^(13c),—C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁴, at each occurrence, isindependently selected from H and C₁₋₄ alkyl; alternatively, two R¹⁴s,along with the carbon atom to which they are attached, join to form aC₃₋₆ carbocyclic ring; R²⁵, at each occurrence, is independentlyselected from H, C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl, NR^(25a)R^(25a),C(O)NR^(25a)R^(25a), NR^(25a)C(O)R^(25b), NR^(25a)C(O)OR^(25b),OC(O)NR^(25a)R^(25a), and (CHR)_(r)C(O)OR^(25b); alternatively, twoR²⁵s, along with the carbon atom or atoms to which they are attached,join to form a C₃₋₆ carbocyclic ring; R^(25a), at each occurrence, isindependently selected from H, and C₁₋₄ alkyl; alternatively, twoR^(25a)S, together with the N to which they are attached, join to form a3-8 membered heterocycle containing 0-1 additional heteroatoms selectedfrom N, O and S; R^(25b), at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl; a is selected from 0and 1; b is selected from 0, 1, 2 and 3; with the proviso that a+b isselected from 1, 2 and 3; c is 1; d is 1; n is selected from 0, 1, 2 and3; p, at each occurrence, is independently selected from 0, 1, and 2; q,at each occurrence, is independently selected from 1, 2, 3, and 4; r, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; s isselected from 0 and 1; and u is selected from 1, 2 and
 3. 2. Thecompound of claim 1, wherein X is selected from O or S; Z is selectedfrom a bond, —C(O)NR⁸—, —NR⁸—, —NR⁸C(O)—, —NR⁸C(O)NH—, —NR⁸SO₂—,—(CR²⁵R²⁵)_(u)—, —CR¹⁴═CR¹⁴—, and —CR²⁵R²⁵C(O)—; wherein neither Z norR¹³ is connected to a carbon atom to which R¹⁰ is attached; bond (g) isa single or double bond; alternatively, when n is equal to 2, the twocarbon atoms may join through a double bond; R¹ is selected from H, R⁶,C₁₋₆ alkyl substituted with 0-3 R⁶, C₆₋₁₀ aryl group substituted with0-5 R⁶, and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁶; R² is selected froma C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a 5-10 memberedheteroaryl system containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R⁷; R⁴ is absent, taken with the nitrogen to whichit is attached to form an N-oxide, or C₁₋₈ alkyl; R⁵ is selected from Hand C₁₋₆ alkyl substituted with 0-2 R^(5e); R^(5e), at each occurrence,is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, F, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, and(CR′R′)_(r)NR^(5f)R^(5f); R^(5f), at each occurrence, is selected from Hand C₁₋₆ alkyl; alternatively, two R^(5f)s, together with the N to whichthey are attached, join to form a 3-8 membered heterocycle containing0-1 additional heteroatoms selected from N, O and S; R⁶, at eachoccurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CR′R′)_(r)C₃₋₆ cycloalkyl, (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,(CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)C(O) (CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)C(O) (CR′R′)_(r)R^(6a),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(6a),(CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6a),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6a), C₁₋₆ haloalkyl,(CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); R^(6a), at each occurrence, isselected from H, methyl, C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2R^(6e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(6e), and a (CR′R′)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);alternatively, two R^(6a)S, together with the N to which they areattached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O, and S; R^(6d), at eachoccurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with0-3 R^(6e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(6e), and a (CR′R′)_(r)-5-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,(CF₂)_(r)CF₃, and (CR′R′)_(r)OC₁₋₅ alkyl; R^(6f), at each occurrence, isselected from H and C₁₋₅ alkyl; at each occurrence, is selected fromC₁₋₈ alkyl, Cl, Br, F, CN, (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,(CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a(CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7a), at eachoccurrence, is independently selected from H, methyl substituted with0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e), a (CR′R′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CR′R′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(7e); alternatively, two R^(7a)s,together with the N to which they are attached, join to form a 3-8membered heterocycle containing 0-1 additional heteroatoms selected fromN, O and S; R^(7b), at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), a(CR′R′)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a(CR′R′)_(r)-4-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7e); R^(7d), at eachoccurrence is selected from methyl, C₂₋₆ alkyl substituted with 0-3R^(7e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(7e), and a (CR′R′)_(r)-5-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,Cl, F, Br, CN, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, OH, C(O)OC₁₋₅alkyl, (CR′R′)_(r)NR^(7f)R^(7f), and acetyl; R^(7f), at each occurrence,is selected from H and C₁₋₅ alkyl; alternatively, two R^(7f)s, togetherwith the N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O andS; R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CR′R′)_(r)phenyl; R′, at each occurrence, is independently, selected from H, methyl, and C₂₋₆ alkyl; R⁸ is selectedfrom H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; R9 is selected from H, C₁₋₄alkyl, C₃₋₄ cycloalkyl, and —C(O)—C₁₋₄ alkyl; R¹⁰ is independentlyselected from H and C₁₋₄ alkyl substituted with 0-1 R^(10b), R^(10b), ateach occurrence, is independently selected from —OH, —SH,—NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; alternatively, twoR^(10c)s, together with the N to which they are attached, join to form a3-8 membered heterocycle containing 0-1 additional heteroatoms selectedfrom N, O and S; R¹² is selected from H and C₁₋₄ alkyl; R¹³, at eachoccurrence, is independently selected from H, —OH, —NH₂, F, Cl, Br,—OR^(13a), —N(R^(13a))₂, and C₁₋₄ alkyl substituted with 0-3 R^(13b);R^(13a) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R^(13b), ateach occurrence, is independently selected from —OH, —SH,—NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c)R^(13c), and —NHC(O)R^(13c);R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁴, at eachoccurrence, is independently selected from H and C₁₋₄alkyl;alternatively, two R¹⁴s, along with the carbon atom to which they areattached, join to form a C₃₋₆ carbocyclic ring; R²⁵, at each occurrence,is independently selected from H, C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl,NR^(25a)R^(25a), C(O)NR^(25a)R^(25a), NR^(25a)C(O)R^(25b),NR^(25a)C(O)OR^(25b), OC(O)NR^(25a)R^(25a), and (CHR)_(r)C(O)OR^(25b);alternatively, two R²⁵s, along with the carbon atom or atoms to whichthey are attached, join to form a C₃₋₆ carbocyclic ring; R^(25a), ateach occurrence, is independently selected from H, and C₁₋₄ alkyl,alternatively, two R^(25a)s, together with the N to which they areattached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R^(25b), at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₆ alkenyl,and C₃₋₆ alkynyl; a is selected from 0 and 1; b is selected from 0 and1; with the proviso that a+b is selected from 1 and 2; c is 1; d is 1; nis selected from 1 and 2; p, at each occurrence, is independentlyselected from 0, 1, and 2; q, at each occurrence, is independentlyselected from 1 and 2; r, at each occurrence, is independently selectedfrom 0, 1, and 2; and s is selected from 0 and 1; and u is selected from1, 2 and
 3. 3. The compound of claim 2, wherein X is O; Z is selectedfrom a bond, —C(O)NR⁸—, —NR⁸— and —NR⁸C(O)—; wherein Z is not connectedto a carbon atom to which R¹⁰ is attached; bond (g) is a single ordouble bond; alternatively, when n is equal to 2, the two carbon atomsmay join through a double bond; R¹ is selected from H, R⁶, and C₁₋₆alkyl substituted with 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl groupsubstituted with 0-5 R⁷, wherein the aryl group is selected from phenyland naphthyl, and a 5-10 membered heteroaryl system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R⁷, whereinthe heteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, phthalazinyl,pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridyl,pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl,thienyl, and tetrazolyl; R⁴ is absent, taken with the nitrogen to whichit is attached to form an N-oxide, or C₁₋₈ alkyl; R⁵ is selected from Hand C₁₋₆ alkyl; R⁶, at each occurrence, is selected from C₁₋₈ alkyl,(CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d),(CR′R′)_(r)C(O) (CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)C(O) (CR′R′)_(r)R^(6a), and(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a); R^(6a), at each occurrence, isselected from H, methyl, C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2R^(6e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(6e), and a (CR′R′)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e);alternatively, two R^(6a)s, together with the N to which they areattached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R^(6d), at eachoccurrence, is selected from methyl and C₂₋₆ alkyl substituted with 0-3R^(6e); R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F,(CF₂)_(r)CF₃, and (CR′R′)_(r)OC₁₋₅ alkyl; R^(6f), at each occurrence, isselected from H and C₁₋₅ alkyl; R⁷, at each occurrence, is selected fromC₁₋₈ alkyl, Cl, Br, F, CN, (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,(CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C1-6 haloalkyl, and a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e);R^(7a), at each occurrence, is independently selected from H, methyl,C₂₋₆ alkyl, a (CR′R′)_(r)C₃₋₁₀ carbocyclic residue substituted with 0-5R^(7e), and a (CR′R′)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);alternatively, two R^(7a)s, together with the N to which they areattached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₈ alkenyl, a (CR′R′)_(r)C₃₋₆carbocyclic residue substituted with 0-3 R^(7e), and a (CR′R′)_(r)-4-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(7e); R^(7d), at each occurrence, isselected from methyl, C₂₋₆ alkyl, a (CR′R′)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(7e), and a (CR′R′)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(7e); R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, Cl, F, Br, CN, (CF₂)_(r)CF₃,(CR′R′)_(r)OC₁₋₅ alkyl, C(O)OC₁₋₅ alkyl, (CR′R′)_(r)NR^(7f)R^(7f), andacetyl; R^(7f), at each occurrence, is selected from H and C₁₋₄ alkyl;R′, at each occurrence, is in dependently, selected from H and methyl;R⁸ is H; R9 is H; R¹⁰ is independently selected from H and C₁₋₄ alkyl;R¹² is H; R¹³, at each occurrence, is H; R¹⁴, at each occurrence, is H;R²⁵, at each occurrence, is independently selected from H, OH, and NH₂;a is 1; b is 0; c is 1; d is 1; n is selected from 1 and 2; p, at eachoccurrence, is independently selected from 0, 1, and 2; q, at eachoccurrence, is 1; r, at each occurrence, is independently selected from0 and 1; and u is selected from 1 and
 2. 4. The compound of claim 3,wherein X is O; Z is selected from a bond and —NR⁹—; wherein Z is notconnected to a carbon atom to which R¹⁰ is attached; bond (g) is asingle or double bond; alternatively, when n is equal to 2, the twocarbon atoms may join through a double bond; R¹ is selected from H, R⁶,and C₁₋₆ alkyl substituted with 0-2 R⁶; R² is a 5-10 membered heteroarylsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R⁷, wherein the heteroaryl is selected from indolyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolinyl,isoxazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl;R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or C₁₋₈ alkyl; R⁵ is selected from H and C₁₋₆ alkyl; R⁶, ateach occurrence, is selected from C₁₋₄ alkyl, (CH₂)_(r)NR^(6a)R^(6a),(CH₂)_(r)OH, (CH₂)_(r)O(CH₂)_(r)R^(6d), (CH₂)_(r)C(O) (CH₂)_(r)R^(6a),(CH₂)_(r)C(O)NR^(6a)R^(6a), (CH₂)_(r)NR^(6f)C(O) (CH₂)_(r)R^(6a), and(CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6a); R^(6a), at each occurrence, isselected from H, C₁₋₄ alkyl, phenyl substituted with 0-3 R^(6e), and a5-10 membered heterocyclic system containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-2 R^(6e); alternatively, twoR^(6a)s, together with the N to which they are attached, join to form aheterocycle wherein the heterocycle is selected from azetidinyl,pyrrolyl, piperidinyl, and morpholinyl; R^(6d), at each occurrence, isselected from C₁₋₄ alkyl; R^(6e), at each occurrence, is selected fromC₁₋₄ alkyl, Cl, F, (CF₂)_(r)CF₃, and (CH₂)_(r)OC₁₋₄ alkyl; R^(6f), ateach occurrence, is selected from H, methyl and ethyl; R⁷ is selectedfrom C₁₋₆ alkyl, phenyl substituted with 0-3 R^(7e), Cl, Br, I, F, CN,NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F, OCF₃, C(O)R^(7b),C(O)OR^(7d), NHC(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

R^(7a), at each occurrence, is independently selected from H and C₁₋₄alkyl; alternatively, two R^(7a)s, together with the N to which they areattached, join to form a heterocycle wherein the heterocycle is selectedfrom azetidinyl, pyrrolyl, piperidinyl, and morpholinyl; R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl, a (CH₂)_(r)C₃₋₆ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7e); R^(7d), at each occurrence, is selectedfrom C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with0-3 R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, CN,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₄ alkyl, C(O)OC₁₋₄ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and acetyl; R^(7f), at each occurrence, isselected from H, and C₁₋₄ alkyl; R⁹ is H; R¹⁰ is independently selectedfrom H and C₁₋₄ alkyl; R¹² is H; R¹³, at each occurrence, is H; R¹⁴, ateach occurrence, is H; a is 1; b is 0; c is 1; d is 1; n is selectedfrom 1 and 2; p, at each occurrence, is in dependently selected from 0,1, and 2; and r, at each occurrence, is independently selected from 0and
 1. 5. The compound of claim 3, wherein X is O; Z is selected from—C(O)NR⁸— and —NR⁸C(O)—; wherein Z is not connected to a carbon atom towhich R¹⁰ is attached; bond (g) is a single or double bond;alternatively, when n is equal to 2, the two carbon atoms may jointhrough a double bond; R¹ is selected from H, R⁶, and C₁₋₆ alkylsubstituted with 0-2 R⁶; R² is selected from a C₆₋₁₀ aryl groupsubstituted with 0-3 R⁷, wherein the aryl group is selected from phenyland naphthyl, and a 5-10 membered heteroaryl system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R⁷, whereinthe heteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, phthalazinyl,pyrazinyl, pyrazolyl, pyrazolotriazinyl, pyridazinyl, pyridyl,pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl,thienyl, and tetrazolyl; R⁴ is absent, taken with the nitrogen to whichit is attached to form an N-oxide, or C₁₋₈ alkyl; R⁵ is selected from Hand C₁₋₆ alkyl; R⁶, at each occurrence, is selected from C₁₋₄ alkyl,(CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH, (CH₂)_(r)O(CH₂)_(r)R^(6d),(CH₂)_(r)C(O) (CH₂)_(r)R^(6a), (CH₂)_(r)C(O)NR^(6a)R^(6a),(CH₂)_(r)NR^(6f)C(O))(CH₂)_(r)R^(6a), and(CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6a); R^(6a), at each occurrence, isselected from H, C₁₋₄ alkyl, phenyl substituted with 0-3 R^(6e), and a5-10 membered heterocyclic system containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-2 R^(6e); alternatively, twoR^(6a)S, together with the N to which they are attached, join to form aheterocycle wherein the heterocycle is selected from azetidinyl,pyrrolyl, piperidinyl, and morpholinyl; R^(6d), at each occurrence, isselected from C₁₋₄ alkyl; R^(6e), at each occurrence, is selected fromC₁₋₄ alkyl, Cl, F, (CF₂)_(r)CF₃, and (CH₂)_(r)OC₁₋₄ alkyl; R^(6f), ateach occurrence, is selected from H, methyl and ethyl; R⁷ is selectedfrom C₁₋₆ alkyl, phenyl substituted with 0-3 R^(7e), Cl, Br, I, F, CN,NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),NR^(7a)C(O)OR^(7d), CF₃, CF₂CF₃, CHF₂, CH₂F, OCF₃, C(O)R^(7b),C(O)OR^(7d), NHC(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

R^(7a), at each occurrence, is independently selected from H and C₁₋₄alkyl; alternatively, two R^(7a)s, together with the N to which they areattached, join to form a heterocycle wherein the heterocycle is selectedfrom azetidinyl, pyrrolyl, piperidinyl, and morpholinyl; R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl, a (CH₂)_(r)C₃₋₆ carbocyclicresidue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(7e); R^(7d), at each occurrence, is selectedfrom C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with0-3 R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, CN,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₄ alkyl, C(O)OC₁₋₄ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and acetyl; R7f, at each occurrence, is selectedfrom H, and C₁₋₄ alkyl; R⁸ is H; R¹⁰ is independently selected from Hand C₁₋₄ alkyl; R¹² is H; R¹³, at each occurrence, is H; R¹⁴, at eachoccurrence, is H; a is 1; b is 0; c is 1; d is 1; n is selected from 1and 2; p, at each occurrence, is in dependently selected from 0, 1, and2; and r, at each occurrence, is independently selected from 0 and
 1. 6.A compound of claim 1, wherein the compound is selected from thetrifluoroacetic acid salt ofendo-N-[1-(octahydrocyclo-penta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoro-methylbenzamide;the trifluoroacetic acid salt ofendo-N-[1-(2-isopropyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoro-methylbenzamide;4-endo-N-[1-(2-isopropyl-4-propyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoromethylbenzamide;4-endo-N-[1-(2-isopropyl-4-propyl-octahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-2-(3-isopropylureido)-5-trifluoromethylbenzamide;N-[1-(2-isopropyl-4-methoxy-methyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxopyrrolidin-3-yl]-3-trifluoromethylbenzamide;N-{1-[2-isopropyl-4-(propane-2-sulfonylmethyl)octahydrocyclopenta[c]pyrrol-5-yl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethylbenzamide;N-[1-(4-benzenesulfonyl-methyl-2-isopropyloctahydrocyclopenta[c]pyrrol-5-yl)-2-oxo-pyrrolidin-3-yl]-3-trifluoromethylbenzamide;or1-(2-isopropyl-4-methoxy-methyloctahydrocyclopenta[c]pyrrol-5-yl)-3-(6-trifluoromethylquinazolin-4-ylamino)pyrrolidin-2-one.7. A pharmaceutical composition comprised of a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof wherein:X is selected from O or S; Z is selected from a bond, —C(O)NR⁸—, —NR⁹—,—NR⁹—CR¹⁴R¹⁴—, —NR⁸C(O)—, —NR⁸C(S)—, —NR⁸C(O)NH—, —NR⁸C(S)NH—, —NR⁸SO₂—,—NR⁸SO₂NH—, —OC(O)NR⁸—, —NR⁸C(O)O—, —(CR²⁵R²⁵)_(u)—, —CR¹⁴═CR¹⁴——,CR²⁵R²⁵C(O)—, —C(O)CR²⁵R²⁵—, —CR²⁵R²⁵C(═N—OR¹⁴)—, —O—CR¹⁴R¹⁴—,—CR¹⁴R¹⁴—O—, —O—, —CR¹⁴R¹⁴—NR⁹—, —S(O)_(p)—, —S(O)_(p)—CR¹⁴R¹⁴—,—CR¹⁴R¹⁴—S(O)_(p)—, and —S(O)_(p)—NR⁹—; wherein neither Z nor R¹³ isconnected to a carbon atom to which R¹⁰ is attached; bond (g) is asingle or double bond; alternatively, when n is equal to 2, the twocarbon atoms may join through a double bond; R¹ is selected from H, R⁶,C₁₋₆ alkyl substituted with 0-3 R⁶, C₂₋₆ alkenyl substituted with 0-3R⁶, C₂₋₆ alkynyl substituted with 0-3 R⁶, C₆₋₁₀ aryl group substitutedwith 0-5 R⁶, and a 5-10 membered heteroaryl system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R⁶; R² isselected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a 5-10membered heteroaryl system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R⁷; R⁴ is absent, taken with the nitrogento which it is attached to form an N-oxide, or selected from C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,(CR′R′)_(q)C(O)R^(4b), (CR′R′)_(q)C(O)NR^(4a)R^(4a),(CR′R′)_(q)C(O)OR^(4b), and a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(4c); R^(4a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,and phenyl; alternatively, two R^(4a)s, together with the N to whichthey are attached, join to form a 3-8 membered heterocycle containing0-1 additional heteroatoms selected from N, O and S; R^(4b), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CR′R′)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl; R^(4c), at eachoccurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CR′R′)_(r)OC₁₋₅ alkyl, (CR′R′)_(r)OH, (CR′R′)_(r)SC₁₋₅alkyl,(CR′R′)_(r)NR^(4a)R^(4a), and (CR′R′)_(r)phenyl; R⁵ is selected from H,C₁₋₆ alkyl substituted with 0-2 R^(5e), —C(O)R^(5b), —C(O)OR^(5b),—C(O)NR^(5f)R^(5f), a C₃₋₁₀ carbocyclic residue substituted with 0-5R^(5e), and a 5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e);R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CR′R′)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(5e), and a (CR′R′)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(5e); R^(5e), each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅ alkyl, OH, SH, (CR′R′)_(r)SC₁₋₅ alkyl,(CR′R′)_(r)NR^(5f)R^(5f), a(CR′R′)_(r)C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(6e); R^(5f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; alternatively, two R^(5f)s, together withthe N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O andS; R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d),(CR′R′)_(r)SC(O) (CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6a), (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6a),(CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),(CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6a), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(6e)S(O)₂(CR′R′)_(r)R^(6a), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CR′R′)_(r)phenyl substituted with 0-3 R^(6e), and a (CR′R′)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(6e); alternatively, two R⁶s onadjacent atoms on R¹ may join to form a cyclic acetal; R^(6a), at eachoccurrence, is selected from H, methyl, C₂₋₆ alkyl substituted with 0-2R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynylsubstituted with 0-2 R^(6e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(6e), and a (CR′R′)_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(6e); alternatively, two R^(6a)s, togetherwith the N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O,and S; R^(6d), at each occurrence, is selected from C₃₋₈ alkenylsubstituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e),methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₂₋₄ haloalkyl, a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and a(CR′R′)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(6e); R^(6e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CR′R′)_(r)OC₁₋₅ alkyl, OH, SH, (CR′R′)_(r)SC₁₋₅ alkyl,(CR′R′)_(r)NR^(6f)R^(6f), and (CR′R′)_(r)phenyl; R^(F), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, andphenyl; alternatively, two R^(6f)s, together with the N to which theyare attached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R⁷, at each occurrence,is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O) (CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(7b),(CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),(CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7d),(CR′R′)_(r)C(NR^(7f))═NR^(7a)R^(7a),(CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f)(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b),(CR′R′)_(r)S(O)₂NR^(7a)R^(7a), (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),(CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a(CR′R′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); alternatively,two R⁷s on adjacent atoms on R² may join to form a cyclic acetal;R^(7a), at each occurrence, is independently selected from H, methylsubstituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with0-2 R^(7e), a (CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(7e), and a (CR′R′)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);alternatively, two R^(7a)s, together with the N to which they areattached, join to form a 3-8 membered heterocycle containing 0-1additional heteroatoms selected from N, O and S; R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(7e),C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with0-2 R^(7e), a (CR′R′)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(7e), and a (CR′R′)_(r)-4-6 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e);R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl substitutedwith 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃,C₂₋₄ haloalkyl, C₂₋₆ alkyl substituted with 0-3 R^(7e), a(CR′R′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a(CR′R′)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CR′R′)_(r)cyclopropyl, Cl, F, Br, CN, (CF₂)_(r)CF₃, (CR′R′)_(r)OC₁₋₅alkyl, OH, C(O)OC₁₋₅ alkyl, (CR′R′)_(r)NR^(7f)R^(7f), and acetyl;R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl, and phenyl; alternatively, two R^(7f)s, together with the Nto which they are attached, join to form a 3-8 membered heterocyclecontaining 0-1 additional heteroatoms selected from N, O and S; R^(7g)is independently selected from —C(O)R^(7b), —C(O)OR^(7d),—C(O)NR^(7f)R^(7f), and (CR′R′)_(r)phenyl; R′, at each occurrence, is independently, selected from H, methyl, and C₂₋₆ alkyl; alternatively, twoR′s, along with the carbon atom to which they are attached, join to forma cyclopropyl ring; R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄cycloalkyl; R9 is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, —C(O)H,and —C(O)—C₁₋₄ alkyl; R¹⁰ is independently selected from H and C₁₋₄alkyl substituted with 0-1 R^(10b), R^(10b), at each occurrence, isindependently selected from —OH, —SH, —NR^(10c)R^(10c),—C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; alternatively, two R^(10c)s, togetherwith the N to which they are attached, join to form a 3-8 memberedheterocycle containing 0-1 additional heteroatoms selected from N, O andS; R¹² is selected from H and C₁₋₄ alkyl; R¹³, at each occurrence, isindependently selected from H, —OH, —NH₂, F, Cl, Br, I, —OR^(13a),—N(R^(13a))₂, and C₁₋₄ alkyl substituted with 0-3 R^(13b); R^(13a) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R^(13b), at eachoccurrence, is independently selected from —OH, —SH, —NR^(13c)R^(13c),—C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) is selected from H,C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁴, at each occurrence, isindependently selected from H and C₁₋₄alkyl; alternatively, two R¹⁴s,along with the carbon atom to which they are attached, join to form aC₃₋₆ carbocyclic ring; R²⁵, at each occurrence, is independentlyselected from H, C₁₋₄alkyl, OH, NH₂, —O—C₁₋₄ alkyl, NR^(25a)R^(25a),C(O)NR^(25a)R^(25a), NR^(25a)C(O)R^(25b), NR^(25a)C(O)OR^(25b),OC(O)NR^(25a)R^(25a), and (CHR)_(r)C(O)OR^(25b); alternatively, twoR²⁵s, along with the carbon atom or atoms to which they are attached,join to form a C₃₋₆ carbocyclic ring; R^(25a), at each occurrence, isindependently selected from H, and C₁₋₄ alkyl; alternatively, twoR^(25a)s, together with the N to which they are attached, join to form a3-8 membered heterocycle containing 0-1 additional heteroatoms selectedfrom N, O and S; R^(25b), at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, C₃₋₆ alkenyl, and C₃₋₆ alkynyl; a is selected from 0and 1; b is selected from 0, 1, 2 and 3; with the proviso that a+b isselected from 1, 2 and 3; c is 1; d is 1; n is selected from 0, 1, 2 and3; p, at each occurrence, is independently selected from 0, 1, and 2; q,at each occurrence, is independently selected from 1, 2, 3, and 4; r, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; s isselected from 0 and 1; and u is selected from 1, 2 and
 3. 8. Thepharmaceutical composition of claim 7 further comprising one or moreactive ingredients.